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Viral Biology

BRIAN D. HOYLE/

ABDEL HAKIM NASR

An understanding of the fundamentals of virus structure, genetics, and replication is critical to virologists and other forensic investigators attempting to identify potential biogenic pathogens that may be exploited as agents in biological warfare or by bioterrorists.

Fundamentals of Viral Biology

Viruses are essentially nonliving repositories of nucleic acid that require the presence of a living prokaryotic or eukaryotic cell for the replication of the nucleic acid. There are a number of different viruses that challenge the human immune system and that may produce disease in humans. In general, a virus is a small, infectious agent that consists of a core of genetic material (either deoxyribonucleic acid [DNA] or ribonucleic acid [RNA]) surrounded by a shell of protein. All viruses share the need for a host in order to replicate their deoxyribonucleic acid (DNA) or ribonucleic acid (RNA). The virus commandeers the host's existing molecules for the nucleic acid replication process. There are a number of different viruses. The differences include the disease symptoms they cause, their antigenic composition, type of nucleic acid residing in the virus particle, the way the nucleic acid is arranged, the shape of the virus, and the fate of the replicated DNA. These differences are used to classify the viruses and have often been the basis on which the various types of viruses were named.

Virology, viral classification, types of viruses. Virology is the discipline of microbiology that is concerned with the study of viruses. Viruses can exist in a variety of hosts. Viruses can infect animals (including humans), plants, fungi, birds, aquatic organisms, protozoa, bacteria, and insects. Some viruses are able to infect several of these hosts, while other viruses are exclusive to one host.

The classification of viruses operates by use of the same structure that governs the classification of bacteria. The International Committee on Taxonomy of Viruses established the viral classification scheme in 1966. From the broadest to the narrowest level of classification, the viral scheme is: Order, Family, Subfamily, Genus, Species,

and Strain/type. To use an example, the virus that was responsible for an outbreak of Ebola hemorrhagic fever in a region of Africa called Kikwit is classified as Order Mononegavirales, Family Filoviridae, Genus Filovirus, and Species Ebola virus Zaire.

In the viral classification scheme, all families end in the suffix viridae, for example Picornaviridae. Genera have the suffix virus. For example, in the family Picornaviridae there are five genera: enterovirus, cardiovirus, rhinovirus, apthovirus, and hepatovirus. The names of the genera typically derive from the preferred location of the virus in the body (for those viral genera that infect humans). As examples, rhinovirus is localized in the nasal and throat passages, and hepatovirus is localized in the liver. Finally, within each genera there can be several species.

There are a number of criteria by which members of one grouping of viruses can be distinguished from those in another group. For the purposes of classification, however, three criteria are paramount. These criteria are the host organism or organisms that the virus utilizes, the shape of the virus particle, and the type and arrangement of the viral nucleic acid.

An important means of classifying viruses concerns the type and arrangement of nucleic acid in the virus particle. Some viruses have two strands of DNA, analogous to the double helix of DNA that is present in prokaryotes such as bacteria and in eukaryotic cells. Some viruses, such as the Adenoviruses, replicate in the nucleus of the host using the replication machinery of the host. Other viruses, such as the Poxviruses, do not integrate in the host genome, but replicate in the cytoplasm of the host. Another example of a double-stranded DNA virus are the Herpesviruses.

Other viruses only have a single strand of DNA. An example is the Parvoviruses. Viruses such as the Parvoviruses replicate their DNA in the host's nucleus. The replication involves the formation of what is termed a negative-sense strand of DNA, which is a blueprint for the subsequent formation of the RNA and DNA used to manufacture the new virus particles.

The genome of other viruses, such as Reoviruses and Birnaviruses, is comprised of double-stranded RNA. Portions of the RNA function independently in the production of a number of so-called messenger RNAs, each of which produces a protein that is used in the production of new viruses.

Still other viruses contain a single strand of RNA. In some of the single-stranded RNA viruses, such as Picornaviruses, Togaviruses, and the Hepatitis A virus, the RNA is read in a direction that is termed "+ sense." The sense strand is used to make the protein products that form the new virus particles. Other single-stranded RNA viruses contain what is termed a negative-sense strand. Examples are the Orthomyxoviruses and the Rhabdoviruses. The negative strand is the blueprint for the formation of the messenger RNAs that are required for production of the various viral proteins.

Still another group of viruses have + sense RNA that is used to make a DNA intermediate. The intermediate is used to manufacture the RNA that is eventually packaged into the new virus particles. The main example is the Retroviruses (e.g. the Human Immunodeficiency viruses). Finally, a group of viruses consist of double-stranded DNA that is used to produce a RNA intermediate. An example is the Hepadnaviruses.

An aspect of virology is the identification of viruses. Often, the diagnosis of a viral illness relies, at least initially, on the visual detection of the virus. For this analysis, samples are prepared for electron microscopy using a technique called negative staining, which highlights surface detail of the virus particles. For this analysis, the shape of the virus is an important feature.

A particular virus will have a particular shape. For example, viruses that specifically infect bacteria, the socalled bacteriophages, look similar to the Apollo lunar lander (LEM spacecraft). A head region containing the nucleic acid is supported on a number of spider-like legs. Upon encountering a suitable bacterial surface, the virus acts like a syringe, to introduce the nucleic acid into the cytoplasm of the bacterium.

Other viruses have different shapes. These include spheres, ovals, worm-like forms, and even irregular (pleomorphic) arrangements. Some viruses, such as the influenza virus, have projections sticking out from the surface of the virus. These are crucial to the infectious process.

As new species of eukaryotic and prokaryotic organisms are discovered, no doubt the list of viral species will continue to grow.

Viral genetics. Viral genetics, the study of the genetic mechanisms that operate during the life cycle of viruses, utilizes biophysical, biological, and genetic analyses to study the viral genome and its variation.

The virus genome consists of only one type of nucleic acid, which could be a single or double stranded DNA or RNA. Single stranded RNA viruses could contain positive-sense (+RNA), which serves directly as mRNA or negative-sense RNA (RNA) that must use an RNA polymerase to synthesize a complementary positive strand to serve as mRNA. Viruses are obligate parasites that are completely dependant on the host cell for the replication and transcription of their genomes as well as the translation of the mRNA transcripts into proteins. Viral proteins usually have a structural function, making up a shell around the genome, but may contain some enzymes that are necessary for the virus replication and life cycle in the host cell. Both bacterial virus (bacteriophages) and animal viruses play an important role as tools in molecular and cellular biology research.

Viruses are classified in two families depending on whether they have RNA or DNA genomes and whether these genomes are double or single stranded. Further subdivision into types takes into account whether the genome consists of a single RNA molecule or many molecules as in the case of segmented viruses. Four types of bacteriophages are widely used in biochemical and genetic research. These are the T phages, the temperate phages typified by bacteriophage lambda, the small DNA phages like M13, and the RNA phages. Animal viruses are subdivided in many classes and types. Class I viruses contain a single molecule of double stranded DNA and are exemplified by adenovirus, simian virus 40 (SV 40), herpes viruses and human papillomaviruses. Class II viruses are also called parvoviruses and are made of single stranded DNA that is copied in to double stranded DNA before transcription in the host cell. Class III viruses are double stranded RNA viruses that have segmented genomes which means that they contain 1012 separate double stranded RNA molecules. The negative strands serve as template for mRNA synthesis. Class IV viruses, typified by poliovirus, have single plus strand genomic RNA that serves as the mRNA. Class V viruses contain a single negative strand RNA which serves as the template for the production of mRNA by specific virus enzymes. Class VI viruses are also known as retroviruses and contain double stranded RNA genome. These viruses have an enzyme called reverse transcriptase that can both copy minus strand DNA from genomic RNA catalyze the synthesis of a complementary plus DNA strand. The resulting double stranded DNA is integrated in the host chromosome and is transcribed by the host own machinery. The resulting transcripts are either used to synthesize proteins or produce new viral particles. These new viruses are released by budding, usually without killing the host cell. Both HIV and HTLV viruses belong to this class of viruses.

Virus genetics is studied by either investigating genome mutations or exchange of genetic material during the life cycle of the virus. The frequency and types of genetic variations in the virus are influenced by the nature of the viral genome and its structure. Especially important are the type of the nucleic acid that influence the potential for the viral genome to integrate in the host, and the segmentation that influence exchange of genetic information through assortment and recombination.

Mutations in the virus genome could either occur spontaneously or be induced by physical and chemical means. Spontaneous mutations that arise naturally as a result of viral replication are either due to a defect in the genome replication machinery or to the incorporation of an analogous base instead of the normal one. Induced virus mutants are obtained by either using chemical mutants like nitrous oxide that acts directly on bases and modify them or by incorporating already modified bases in the virus genome by adding these bases as substrates during virus replication. Physical agents such as ultraviolet light and x rays can also be used in inducing mutations. Genotypically, the induced mutations are usually point mutations, deletions, and rarely insertions. The phenotype of the induced mutants is usually varied. Some mutants are conditional lethal mutants. These could differ from the wild type virus by being sensitive to high or low temperature. A low temperature mutant would for example grow at 31°C but not at 38°, while the wild type will grow at both temperatures. A mutant could also be obtained that grows better at elevated temperatures than the wild type virus. These mutants are called hot mutants and may be more dangerous for the host because fever, which usually slows the growth of wild type virus, is ineffective in controlling them. Other mutants that are usually generated are those that show drug resistance, enzyme deficiency or an altered pathogenicity or host range. Some of these mutants cause milder symptoms compared to the parental virulent virus and usually have potential in vaccine development as exemplified by some types of influenza vaccines.

Besides mutation, new genetic variants of viruses also arise through exchange of genetic material by recombination and reassortment. Classical recombination involves breaking of covalent bonds within the virus nucleic acid and exchange of some DNA segments followed by rejoining of the DNA break. This type of recombination is almost exclusively reserved to DNA viruses and retroviruses. RNA viruses that do not have a DNA phase rarely use this mechanism. Recombination usually enables a virus to pick up genetic material from similar viruses and even from unrelated viruses and the eukaryotic host cells. Exchange of genetic material with the host is especially common with retroviruses. Reassortment is a non-classical kind of recombination that occurs if two variants of a segmented virus infect the same cell. The resulting progeny virions may get some segments from one parent and some from the other. All known segmented virus that infect humans are RNA viruses. The process of reassortment is very efficient in the exchange of genetic material and is used in the generation of viral vaccines especially in the case of influenza live vaccines. The ability of viruses to exchange genetic information through recombination is the basis for virus-based vectors in recombinant DNA technology and hold great promises in the development of gene therapy. Viruses are attractive as vectors in gene therapy because they can be targeted to specific tissues in the organs that the virus usually infect and because viruses do not need special chemical reagents called transfectants that are used to target a plasmid vector to the genome of the host.

Genetic variants generated through mutations, recombination or reassortment could interact with each other if they infected the same host cell and prevent the appearance of any phenotype. This phenomenon, where each mutant provide the missing function of the other while both are still genotypically mutant, is known as complementation. It is used as an efficient tool to determine if mutations are in a unique or in different genes and to reveal the minimum number of genes affecting a function. Temperature sensitive mutants that have the same mutation in the same gene will for example not be able to complement each other. It is important to distinguish complementation from multiplicity reactivation where a higher dose of inactivated mutants will be reactivated and infect a cell because these inactivated viruses cooperate in a poorly understood process. This reactivation probably involves both a complementation step that allows defective viruses to replicate and a recombination step resulting in new genotypes and sometimes regeneration of the wild type. The viruses that need complementation to achieve an infectious cycle are usually referred to as defective mutants and the complementing virus is the helper virus. In some cases, the defective virus may interfere with and reduce the infectivity of the helper virus by competing with it for some factors that are involved in the viral life cycle. These defective viruses called "defective interfering" are sometimes involved in modulating natural infections. Different wild type viruses that infect the same cell may exchange coat components without any exchange of genetic material. This phenomenon, known as phenotypic mixing is usually restricted to related viruses and may change both the morphology of the packaged virus and the tropism or tissue specificity of these infectious agents.

Virus replication. Viral replication refers to the means by which virus particles make new copies of themselves. Although precise mechanisms vary, viruses cause disease by infecting a host cell and commandeering the host cell's synthetic capabilities to produce more viruses. The newly made viruses then leave the host cell, sometimes killing it in the process, and proceed to infect other cells within the host.

Viruses cannot replicate by themselves. They require the participation of the replication equipment of the host cell that they infect in order to replicate. The molecular means by which this replication takes place varies, depending upon the type of virus.

Viral replication can be divided up into three phases: initiation, replication, and release.

The initiation phase occurs when the virus particle attaches to the surface of the host cell, penetrates into the cell and undergoes a process known as uncoating, where the viral genetic material is released from the virus into the host cell's cytoplasm. The attachment typically involves the recognition of some host surface molecules by a corresponding molecule on the surface of the virus. These two molecules can associate tightly with one another, binding the virus particle to the surface. A well-studied example is the haemagglutinin receptor of the influenzae virus. The receptors of many other viruses have also been characterized.

A virus particle may have more than one receptor molecule, to permit the recognition of different host molecules, or of different regions of a single host molecule. The molecules on the host surface that are recognized tend to be those that are known as glycoproteins. For example, the human immunodeficiency virus recognizes a host glycoprotein called CD4. Cells lacking CD4 cannot, for example, bind the HIV particle.

Penetration of the bound virus into the host interior requires energy. Accordingly, penetration is an active step, not a passive process. The penetration process can occur by several means. For some viruses, the entire particle is engulfed by a membrane-enclosed bag produced by the host (a vesicle) and is drawn into the cell. This process is called endocytosis. Polio virus and orthomyxovirus enters a cell via this route. A second method of penetration involves the fusion of the viral membrane with the host membrane. Then the viral contents are directly released into the host. HIV, paramyxoviruses, and herpes viruses use this route. Finally, but more rarely, a virus particle can be transported across the host membrane. For example, poliovirus can cause the formation of a pore through the host membrane. The viral DNA is then released into the pore and passes across to the inside of the host cell.

Once inside the host, the viruses that have entered via endocytosis or transport across the host membrane need to release their genetic material. With poxvirus, viral proteins made after the entry of the virus into the host are needed for uncoating. Other viruses, such as adenoviruses, herpesviruses, and papovaviruses associate with the host membrane that surrounds the nucleus prior to uncoating. They are guided to the nuclear membrane by the presence of so-called nuclear localization signals, which are highly charged viral proteins. The viral genetic material then enters the nucleus via pores in the membrane. The precise molecular details of this process remains unclear for many viruses.

For animal viruses, the uncoating phase is also referred to as the eclipse phase. No infectious virus particles can be detected during that 10 to 12 hour period of time.

In the replication, or synthetic, phase the viral genetic material is converted to deoxyribonucleic acid (DNA), if the material originally present in the viral particle is ribonucleic acid (RNA). This so-called reverse transcription process needs to occur in retroviruses, such as HIV. The DNA is imported into the host nucleus where the production of new DNA, RNA, and protein can occur. The replication phase varies greatly from virus type to virus type. However, in general, proteins are manufactured to ensure that the cell's replication machinery is harnessed to permit replication of the viral genetic material, to ensure that this replication of the genetic material does indeed occur, and to ensure that this newly made material is properly packaged into new virus particles.

Replication of the viral material can be a complicated process, with different stretches of the genetic material being transcribed simultaneously, with some of these gene products required for the transcription of other viral genes. Also replication can occur along a straight stretch of DNA, or when the DNA is circular (the so-called "rolling circle" form). RNA-containing viruses must also undergo a reverse transcription from DNA to RNA prior to packaging of the genetic material into the new virus particles.

In the final stage, the viral particles are assembled and exit the host cell. The assembly process can involve helper proteins, made by the virus or the host. These are also called chaperones. Other viruses, such as tobacco mosaic virus, do not need these helper chaperones, as the proteins that form the building blocks of the new particles spontaneously self-assemble. In most cases, the assembly of viruses is symmetrical; that is, the structure is the same throughout the viral particle. For example, in the tobacco mosaic virus, the proteins constituents associate with each other at a slight angle, producing a symmetrical helix. Addition of more particles causes the helix to coil "upward" forming a particle. An exception to the symmetrical assembly is the bacteriophage. These viruses have a head region that is supported by legs that are very different in structure. Bacteriophage assembly is very highly coordinated, involving the separate manufacture of the component parts and the direct fitting together of the components in a sequential fashion.

Release of viruses can occur by a process called budding. A membrane "bleb" containing the virus particle is formed at the surface of the cell and is pinched off. For herpes virus this is in fact how the viral membrane is acquired. In other words, the viral membrane is a host-derived membrane. Other viruses, such as bacteriophage, may burst the host cell, spewing out the many progeny virus particles. But many viruses do not adopt such a host destructive process, as it limits the time of an infection due to destruction of the host cells needed for future replication.

FURTHER READING:

BOOKS:

Doerfler, Walter, and Petra Bohm, eds. Virus Strategies: Molecular Biology and Pathenogenesis. New York: VCH, 1993.

Flint, S. J., et al. Principles of Virology: Molecular Biology, Pathogenesis, and Control. Washington: American Society for Microbiology, 1999.

Kurstak, Edouard, ed. Control of Virus Diseases. New York: Marcel Dekker, 1993.

Richman, D. D., and R. J. Whitley. Clinical Virology. 2nd ed. Washington: American Society for Microbiology, 2002.

Thomas, D. Brian. Viruses and the Cellular Immune Response. New York: Marcel Dekker, 1993.

PERIODICALS:

Peters, C. J., and J. W. LeDuc. "An Introduction to Ebola: The Virus and the Disease." The Journal of Infectious Diseases no. 179 (Supplement 1, February 1999): ixxvi.

ELECTRONIC:

Biology Pages. "Viruses." 2002. <http://www.ultranet.com/~jkimball/BiologyPages/V/Viruses.htm>l> (April 12, 2003).

SEE ALSO

Bacterial Biology
Biological and Toxin Weapons Convention
Biological Warfare
Biological Weapons, Genetic Identification
Bioshield Project
Bioterrorism
Bioterrorism, Protective Measures

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Viruses and responses to viral infection

There are a number of different viruses that challenge the human immune system and that may produce disease in humans. In common, viruses are small, infectious agents that consist of a core of genetic materialeither deoxyribonucleic acid (DNA ) or ribonucleic acid (RNA)surrounded by a shell of protein. Although precise mechanisms vary, viruses cause disease by infecting a host cell and commandeering the host cell's synthetic capabilities to produce more viruses. The newly made viruses then leave the host cell, sometimes killing it in the process, and proceed to infect other cells within the host. Because viruses invade cells, drug therapies have not yet been designed to kill viruses, although some have been developed to inhibit their growth. The human immune system is the main defense against a viral disease.

Bacterial viruses, called bacteriophages, infect a variety of bacteria , such as Escherichia coli, a bacteria commonly found in the human digestive tract. Animal viruses cause a variety of fatal diseases. Acquired Immunodeficiency Syndrome (AIDS ) is caused by the Human Immunodeficiency Virus (HIV ); hepatitis and rabies are viral diseases; and hemorrhagic fevers , which are characterized by severe internal bleeding, are caused by filoviruses. Other animal viruses cause some of the most common human diseases. Often these diseases strike in childhood. Measles , mumps , and chickenpox are viral diseases. The common cold and influenza are also caused by viruses. Finally, some viruses can cause cancer and tumors. One such virus, Human T-cell Leukemia Virus (HTLV ), was only recently discovered and its role in the development of a particular kind of leukemia is still being elucidated.

Although viral structure varies considerably between the different types of viruses , all viruses share some common characteristics. All viruses contain either RNA or DNA surrounded by a protective protein shell called a capsid. Some viruses have a double strand of DNA, others a single strand of DNA. Other viruses have a double strand of RNA or a single strand of RNA. The size of the genetic material of viruses is often quite small. Compared to the 100,000 genes that exist within human DNA, viral genes number from 10 to about 200 genes.

Viruses contain such small amounts of genetic material because the only activity that they perform independently of a host cell is the synthesis of the protein capsid. In order to reproduce, a virus must infect a host cell and take over the host cell's synthetic machinery. This aspect of virusesthat the virus does not appear to be "alive" until it infects a host cellhas led to controversy in describing the nature of viruses. Are they living or non-living? When viruses are not inside a host cell, they do not appear to carry out many of the functions ascribed to living things, such as reproduction, metabolism , and movement. When they infect a host cell, they acquire these capabilities. Thus, viruses are both living and non-living. It was once acceptable to describe viruses as agents that exist on the boundary between living and non-living; however, a more accurate description of viruses is that they are either active or inactive, a description that leaves the question of life behind altogether.

All viruses consist of genetic material surrounded by a capsid; but variations exist within this basic structure. Studding the envelope of these viruses are protein "spikes." These spikes are clearly visible on some viruses, such as the influenza viruses; on other enveloped viruses, the spikes are extremely difficult to see. The spikes help the virus invade host cells. The influenza virus, for instance, has two types of spikes. One type, composed of hemagglutinin protein (HA), fuses with the host cell membrane, allowing the virus particle to enter the cell. The other type of spike, composed of the protein neuraminidase (NA), helps the newly formed virus particles to bud out from the host cell membrane.

The capsid of viruses is relatively simple in structure, owing to the few genes that the virus contains to encode the capsid. Most viral capsids consist of a few repeating protein subunits. The capsid serves two functions: it protects the viral genetic material and it helps the virus introduce itself into the host cell. Many viruses are extremely specific, targeting only certain cells within the plant or animal body. HIV, for instance, targets a specific immune cell, the T helper cell. The cold virus targets respiratory cells, leaving the other cells in the body alone. How does a virus "know" which cells to target? The viral capsid has special receptors that match receptors on their targeted host cells. When the virus encounters the correct receptors on a host cell, it "docks" with this host cell and begins the process of infection and replication.

Most viruses are rod-shaped or roughly sphere-shaped. Rod-shaped viruses include tobacco mosaic virus and the filoviruses. Although they look like rods under a microscope , these viral capsids are actually composed of protein molecules arranged in a helix. Other viruses are shaped somewhat like spheres, although many viruses are not actual spheres. The capsid of the adenovirus, which infects the respiratory tract of animals, consists of 20 triangular faces. This shape is called an icosahedron. HIV is a true sphere, as is the influenza virus.

Some viruses are neither rod-nor sphere-shaped. The poxviruses are rectangular, looking somewhat like bricks. Parapoxviruses are ovoid. Bacteriophages are the most unusually shaped of all viruses. A bacteriophage consists of a head region attached to a sheath. Protruding from the sheath are tail fibers that dock with the host bacterium. Bacteriophage structure is eminently suited to the way it infects cells. Instead of the entire virus entering the bacterium, the bacteriophage injects its genetic material into the cell, leaving an empty capsid on the surface of the bacterium.

Viruses are obligate intracellular parasites , meaning that in order to replicate, they need to be inside a host cell. Viruses lack the machinery and enzymes necessary to reproduce; the only synthetic activity they perform on their own is to synthesize their capsids.

The infection cycle of most viruses follows a basic pattern. Bacteriophages are unusual in that they can infect a bacterium in two ways (although other viruses may replicate in these two ways as well). In the lytic cycle of replication, the bacteriophage destroys the bacterium it infects. In the lysogenic cycle, however, the bacteriophage coexists with its bacterial host and remains inside the bacterium throughout its life, reproducing only when the bacterium itself reproduces.

An example of a bacteriophage that undergoes lytic replication inside a bacterial host is the T4 bacteriophage, which infects E. coli. T4 begins the infection cycle by docking with an E. coli bacterium. The tail fibers of the bacteriophage make contact with the cell wall of the bacterium, and the bacteriophage then injects its genetic material into the bacterium. Inside the bacterium, the viral genes are transcribed. One of the first products produced from the viral genes is an enzyme that destroys the bacterium's own genetic material. Now the virus can proceed in its replication unhampered by the bacterial genes. Parts of new bacteriophages are produced and assembled. The bacterium then bursts, and the new bacteriophages are freed to infect other bacteria. This entire process takes only 2030 minutes.

In the lysogenic cycle, the bacteriophage reproduces its genetic material but does not destroy the host's genetic material. The bacteriophage called lambda, another E. coli -infecting virus, is an example of a bacteriophage that undergoes lysogenic replication within a bacterial host. After the viral DNA has been injected into the bacterial host, it assumes a circular shape. At this point the replication cycle can become either lytic or lysogenic. In a lysogenic cycle the circular DNA attaches to the host cell genome at a specific place. This combination host-viral genome is called a prophage. Most of the viral genes within the prophage are repressed by a special repressor protein, so they do not encode the production of new bacteriophages. However, each time the bacterium divides, the viral genes are replicated along with the host genes. The bacterial progeny are thus lysogenically infected with viral genes.

Interestingly, bacteria that contain prophages can be destroyed when the viral DNA is suddenly triggered to undergo lytic replication. Radiation and chemicals are often the triggers that initiate lytic replication. Another interesting aspect of prophages is the role they play in human diseases. The bacteria that cause diphtheria and botulism both harbor viruses. The viral genes encode powerful toxins that have devastating effects on the human body. Without the infecting viruses, these bacteria may well be innocuous. It is the presence of viruses that makes these bacterial diseases so lethal.

Scientists have classified viruses according to the type of genetic material they contain. Broad categories of viruses include double-stranded DNA viruses, single-stranded DNA viruses, double-stranded RNA viruses, and single stranded RNA viruses. For the description of virus types that follows, however, these categories are not used. Rather, viruses are described by the type of disease they cause.

Poxviruses are the most complex kind of viruses known. They have large amounts of genetic material and fibrils anchored to the outside of the viral capsid that assist in attachment to the host cell. Poxviruses contain a double strand of DNA.

Viruses cause a variety of human diseases, including smallpox and cowpox . Because of worldwide vaccination efforts, smallpox has virtually disappeared from the world, with the last known case appearing in Somalia in 1977. The only places on Earth where smallpox virus currently exists are two labs: the Centers for Disease Control in Atlanta and the Research Institute for Viral Preparation in Moscow. Prior to the eradication efforts begun by the World Health Organization in 1966, smallpox was one of the most devastating of human diseases. In 1707, for instance, an outbreak of smallpox killed 18,000 of Iceland's 50,000 residents. In Boston in 1721, smallpox struck 5,889 of the city's 12,000 inhabitants, killing 15% of those infected.

Edward Jenner (17491823) is credited with developing the first successful vaccine against a viral disease, and that disease was smallpox. A vaccine works by eliciting an immune response. During this immune response, specific immune cells, called memory cells, are produced that remain in the body long after the foreign microbe present in a vaccine has been destroyed. When the body again encounters the same kind of microbe, the memory cells quickly destroy the microbe. Vaccines contain either a live, altered version of a virus or bacteria, or they contain only parts of a virus or bacteria, enough to elicit an immune response.

In 1797, Jenner developed his smallpox vaccine by taking infected material from a cowpox lesion on the hand of a milkmaid. Cowpox was a common disease of the era, transmitted through contact with an infected cow. Unlike smallpox, however, cowpox is a much milder disease. Using the cowpox pus, he inoculated an eight-year-old boy. Jenner continued his vaccination efforts through his lifetime. Until 1976, children were vaccinated with the smallpox vaccine, called vaccinia. Reactions to the introduction of the vaccine ranged from a mild fever to severe complications, including (although very rarely) death. In 1976, with the eradication of smallpox complete, vaccinia vaccinations for children were discontinued, although vaccinia continues to be used as a carrier for recombinant DNA techniques. In these techniques, foreign DNA is inserted in cells. Efforts to produce a vaccine for HIV, for instance, have used vaccinia as the vehicle that carries specific parts of HIV.

Herpesviruses are enveloped, double-stranded DNA viruses. Of the more than 50 herpes viruses that exist, only eight cause disease in humans. These include the human herpes virus types 1 and 2 that cause cold sores and genital herpes; human herpes virus 3, or varicella-zoster virus (VZV), that causes chickenpox and shingles; cytomegalovirus (CMV), a virus that in some individuals attacks the cells of the eye and leads to blindness; human herpes virus 4, or Epstein-Barr virus (EBV), which has been implicated in a cancer called Burkitt's lymphoma; and human herpes virus types 6 and 7, newly discovered viruses that infect white blood cells. In addition, herpes B virus is a virus that infects monkeys and can be transmitted to humans by handling infected monkeys.

Adenoviruses are viruses that attack respiratory, intestinal, and eye cells in animals. More than 40 kinds of human adenoviruses have been identified. Adenoviruses contain double-stranded DNA within a 20-faceted capsid. Adenoviruses that target respiratory cells cause bronchitis, pneumonia , and tonsillitis. Gastrointestinal illnesses caused by adenoviruses are usually characterized by diarrhea and are often accompanied by respiratory symptoms. Some forms of appendicitis are also caused by adenoviruses. Eye illnesses caused by adenoviruses include conjunctivitis, an infection of the eye tissues, as well as a disease called pharyngoconjunctival fever, a disease in which the virus is transmitted in poorly chlorinated swimming pools.

Human papoviruses include two groups: the papilloma viruses and the polyomaviruses. Human papilloma viruses (HPV) are the smallest double-stranded DNA viruses. They replicate within cells through both the lytic and the lysogenic replication cycles. Because of their lysogenic capabilities, HPV-containing cells can be produced through the replication of those cells that HPV initially infects. In this way, HPV infects epithelial cells, such as the cells of the skin. HPVs cause several kinds of benign (non-cancerous) warts, including plantar warts (those that form on the soles of the feet) and genital warts. However, HPVs have also been implicated in a form of cervical cancer that accounts for 7% of all female cancers.

HPV is believed to contain oncogenes, or genes that encode for growth factors that initiate the uncontrolled growth of cells. This uncontrolled proliferation of cells is called cancer. When the HPV oncogenes within an epithelial cell are activated, they cause the epithelial cell to proliferate. In the cervix (the opening of the uterus), the cell proliferation manifests first as a condition called cervical neoplasia. In this condition, the cervical cells proliferate and begin to crowd together. Eventually, cervical neoplasia can lead to full-blown cancer.

Polyomaviruses are somewhat mysterious viruses. Studies of blood have revealed that 80% of children aged five to none years have antibodies to these viruses, indicating that they have at some point been exposed to polyomaviruses. However, it is not clear what disease this virus causes. Some evidence exists that a mild respiratory illness is present when the first antibodies to the virus are evident. The only disease that is certainly caused by polyomavirses is called progressive multifocal leukoencephalopathy (PML), a disease in which the virus infects specific brain cells called the oligodendrocytes. PML is a debilitating disease that is usually fatal, and is marked by progressive neurological degeneration. It usually occurs in people with suppressed immune systems, such as cancer patients and people with AIDS.

The hepadnaviruses cause several diseases, including hepatitis B. Hepatitis B is a chronic, debilitating disease of the liver and immune system. The disease is much more serious than hepatitis A for several reasons: it is chronic and long-lasting; it can cause cirrhosis and cancer of the liver; and many people who contract the disease become carriers of the virus, able to transmit the virus through body fluids such as blood, semen, and vaginal secretions.

The hepatitis B virus (HBV) infects liver cells and has one of the smallest viral genomes. A double-stranded DNA virus, HBV is able to integrate its genome into the host cell's genome. When this integration occurs, the viral genome is replicated each time the cell divides. Individuals who have integrated HBV into their cells become carriers of the disease. Recently, a vaccine against HBV was developed. The vaccine is especially recommended for health care workers who through exposure to patient's body fluids are at high risk for infection.

Parvoviruses are icosahedral, single-stranded DNA viruses that infect a wide variety of mammals. Each type of parvovirus has its own host. For instance, one type of parvovirus causes disease in humans; another type causes disease in cats; while still another type causes disease in dogs. The disease caused by parvovirus in humans is called erythremia infectiosum, a disease of the red blood cells that is relatively rare except for individuals who have the inherited disorder sickle cell anemia. Canine and feline parvovirus infections are fatal, but a vaccine against parvovirus is available for dogs and cats.

Orthomyxoviruses cause influenza ("flu"). This highly contagious viral infection can quickly assume epidemic proportions, given the right environmental conditions. An influenza outbreak is considered an epidemic when more than 10% of the population is infected. Antibodies that are made against one type of rhinovirus are often ineffective against other types of viruses. For this reason, most people are susceptible to colds from season to season.

These helical, enveloped, single-stranded RNA viruses cause pneumonia, croup, measles, and mumps in children. A vaccine against measles and mumps has greatly reduced the incidence of these diseases in the United States. In addition, a paramyxovirus called respiratory syncytial virus (RSV) causes bronchiolitis (an infection of the bronchioles) and pneumonia.

Flaviviruses (from the Latin word meaning "yellow") cause insect-carried diseases including yellow fever , an often-fatal disease characterized by high fever and internal bleeding. Flaviviruses are single-stranded RNA viruses.

The two filoviruses, Ebola virus and Marburg virus, are among the most lethal of all human viruses. Both cause severe fevers accompanied by internal bleeding, which eventually kills the victim. The fatality rate of Marburg is about 60%, while the fatality rate of Ebola virus approaches 90%. Both are transmitted through contact with body fluids. Marburg and Ebola also infect primates.

Rhabdoviruses are bullet-shaped, single-stranded RNA viruses. They are responsible for rabies, a fatal disease that affects dogs, rodents, and humans.

Retroviruses are unique viruses. They are double-stranded RNA viruses that contain an enzyme called reverse transcriptase. Within the host cell, the virus uses reverse transcriptase to make a DNA copy from its RNA genome. In all other organisms, RNA is synthesized from DNA. Cells infected with retroviruses are the only living things that reverse this process.

The first retroviruses discovered were viruses that infect chickens. The Rous sarcoma virus, discovered in the 1950s by Peyton Rous (18791970), was also the first virus that was linked to cancer. However, it was not until 1980 that the first human retrovirus was discovered. Called Human T-cell Leukemia Virus (HTLV), this virus causes a form of leukemia called adult T-cell leukemia. In 1983, another human retrovirus, Human Immunodeficiency Virus, the virus responsible for AIDS, was discovered independently by two researchers. Both HIV and HTLV are transmitted in body fluids.

See also Bacteria and bacterial infection; Epidemics, viral; Immune stimulation, as a vaccine; Immunity, active, passive, and delayed; Immunology; Virology; Virus replication

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Viral Infections

How Are Viruses Different from Bacteria?

How Do Viruses Infect the Body?

How Long Do Viral Infections Last?

How Do Viruses Cause Illness?

How Are Viral Infections Diagnosed and Treated?

How Are Viral Infections Prevented?

Viral infections occur when viruses enter cells in the body and begin reproducing, often causing illness. Viruses are tiny germs that can reproduce only by invading a living cell.

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Infection

Polymerase chain reaction

Virology

How Are Viruses Different from Bacteria?

Viruses are far smaller than bacteria. They are so small that they could not be seen until the electron microscope was invented in the 1940s. Unlike most bacteria, viruses are not complete cells that can function on their own. They cannot convert carbohydrates to energy, the way that bacteria and other living cells do. Viruses depend on other organisms for energy. And viruses cannot reproduce unless they get inside a living cell. Most viruses consist only of tiny particles of nucleic acid (the material that makes up genes) surrounded by a coat of protein. Some have an outer envelope as well.

Are Viruses Alive?

It would seem to be a simple matter to tell if something is alive. But biologists disagree on whether viruses are a form of life.

Viruses lack certain features that other forms of life have. They cannot convert carbohydrates, proteins, or fats into energy, a process called metabolism. They cannot reproduce on their own, but must enter a living cell and use the host cells energy. On the other hand, like all life forms, viruses do have genes made of nucleic acid that contain the information they need to reproduce.

Biologists have an elaborate way of classifying every form of life. Each is grouped into a kingdom (such as the Animal Kingdom) and smaller subcategories called the phylum, class, genus, and species.

Bacteria and fungi each have a kingdom of their own, but viruses are left out of this system. Many biologists think that, unlike the forms of life grouped into kingdoms, viruses did not evolve (develop) as a group. Instead, viruses may have developed individually from the kind of cells they now infect animal cells, plant cells, or bacteria.

Thousands Of viruses

There are thousands of viruses, and in humans they cause a wide range of diseases. For instance, rhinoviruses cause colds, influenza viruses cause flu, adenoviruses cause various respiratory problems, and rotaviruses cause gastroenteritis. Polioviruses can make their way to the spinal cord and cause paralysis, while coxsackieviruses (sometimes written as Coxsackie viruses) and echoviruses sometimes infect the heart or the membranes surrounding the spinal cord or lungs. Herpesviruses cause cold sores, chickenpox, and genital herpes, a sexually transmitted disease. Other viruses cause a variety of conditions from measles and mumps to AIDS.

The bodys defense system

Most viruses do not cause serious diseases and are killed by the bodys immune systemits network of natural defenses. In many cases, people never even know they have been infected. But unlike bacteria, which can be killed by antibiotics, most viruses are not affected by existing medicines. Fortunately, scientists have been able to make vaccines, which help the body develop natural defenses to prevent many viral infections.

How Do Viruses Infect the Body?

Viruses can enter the human body through any of its openings, but most often they use the nose and mouth. Once inside, the virus attaches itself to the outside of the kind of cell it attacks, called a host cell. For example, a rhinovirus attacks cells in the nose, while an enterovirus binds to cells in the stomach and intestines. Then the virus works its way through the host cells outer membrane.

After entering the cell, the virus begins making identical viruses from the host cells protein. These new viruses may make their way back out through the host cells membrane, sometimes destroying the cell, and then attacking new host cells. This process continues until the body develops enough antibodies* and other defenses to defeat the viral invaders.

* antibodies
are proteins made by the bodys immune system to target a specific kind of germ or other foreign substance.

Not all viruses attack only one part of the body, causing what is called a localized infection. Some viruses spread through the bloodstream or the nerves, attacking cells throughout the body. For instance, HIV, the human immunodeficiency virus that causes AIDS, attacks certain cells of the immune system that are located throughout the body.

How Long Do Viral Infections Last?

In most types of viral infection, the immune system clears the virus from the body within days to a few weeks. But some viruses cause persistent or latent* infections, which can last for years. In these cases, a person may get infected and seem to recover or may not be aware of being infected at all. Then years later, the illness will occur again, or symptoms will start for the first time. Viruses that can cause latent infections include herpesviruses, Hepatitis B and C viruses, and HIV.

* latent
infections are dormant or hidden illnesses that do not show the signs and symptoms of active diseases.

How Do Viruses Cause Illness?

Viruses can cause illness by destroying or interfering with the functioning of large numbers of important cells. Sometimes, as mentioned earlier, the cell is destroyed when the newly created viruses leave it. Sometimes the virus keeps the cell from producing the energy it needs to live, or the virus upsets the cells chemical balance in some other way. Sometimes the virus seems to trigger a mysterious process called programmed cell death or apoptosis (ap-op-TO-sis) that kills the cell.

Some persistent or latent viral infections seem to transform cells into a cancerous state that makes them grow out of control. It has been estimated that 10 to 20 percent of cancers are caused by viral infections. The most common are liver cancer caused by persistent infection with Hepatitis B or Hepatitis C virus, and cancer of the cervix (the bottom of a womans uterus or womb), linked to certain strains of the human papillomavirus.

Sometimes a viral illness is caused not by the virus itself, but by the bodys reaction to it. The immune system may kill cells in order to get rid of the virus that is inside them. This can cause serious illness if the cells being killed are very important to the bodys functioning, like those in the lungs or central nervous system, or if the cells cannot reproduce quickly enough to replace the ones being destroyed.

What Is a 24-Hour Virus?

When people have a mild illness perhaps fever and an upset stomach, perhaps nausea and diarrheathey often say they have a 24-hour virus or a stomach virus. Many viruses can cause these kinds of symptoms, but there are many other possible causes as well, including bacterial infection or bacterial food poisoning. People usually recover from these brief or mild illnesses before doctors can do the tests that determine the causes. So a stomach virus may or may not be a virus at all.

How Are Viral Infections Diagnosed and Treated?

Symptoms

Symptoms vary widely, depending on the virus and the organs involved. Many viruses, like many bacteria, cause fever, and either respiratory symptoms (coughing and sneezing) or intestinal symptoms (nausea, vomiting, diarrhea). Viral illnesses often cause high fevers in young children, even when the illnesses are not dangerous.

Diagnosis

Some viral infections, such as influenza, the common cold, and chickenpox, are easily recognized by their symptoms and no lab tests are needed. For many others, such as viral hepatitis, AIDS, and mononucleosis, a blood sample is analyzed for the presence of specific antibodies to the virus. If present, these antibodies help confirm the diagnosis. In some cases, a virus may be grown in the laboratory, using a technique called tissue culture, or identified by its nucleic acid, using a technique called polymerase chain reaction (PCR). Tests like PCR or tissue culture are used when antibody tests are not precise enough or when the actual amount of a virus in the body must be determined.

Treatment

Viruses cannot be treated with the antibiotics that kill bacteria. Fortunately, a few drugs, such as ribavirin and acyclovir, can control the spread of viral invaders without destroying host cells. Intense research to find better treatments for AIDS has led to development of many drugs that help fight the virus. Unfortunately, none of these drugs has been able to treat viral infections as effectively as antibiotics treat bacterial infections.

How Are Viral Infections Prevented?

Hygiene and sanitation

The first step in preventing the spread of viral infections is simply to practice good hygiene. This means washing the hands often, and eating only food that has been prepared properly. It also means building and maintaining facilities for getting rid of sewage safely and for providing clean drinking water.

Vaccination

Another important preventive measure is immunizing people against viruses. This involves giving people vaccines that stimulate the immune system to make antibodies, proteins that target a specific germ. Vaccines to prevent Hepatitis B, polio, mumps, measles, rubella (German measles), and chickenpox are usually given to babies and young children in the United States. Vaccines also can prevent influenza and Hepatitis A.

Vaccines are useful only against certain kinds of viruses. For example, the polioviruses that cause poliomyelitis (polio), a great crippler of children in the past, are few in number and relatively stable. So it was possible in the 1950s to make a vaccine that protects children from getting polio (although the illness still occurs in the developing world where fewer children are vaccinated). On the other hand, influenza viruses change in minor ways every few years and in a major way about every ten years, so a flu vaccine is useful for only a year or two.

One reason a vaccine for the common cold has never been developed is that there are at least a hundred different rhinoviruses that cause colds, and so far it has not been possible to make a vaccine that works against all of them. A similar problem with HIV, which has many different and fast-changing strains (variations), is one of several reasons why progress toward an AIDS vaccine has been slow.

See also

Bronchitis

Cancer

Encephalitis

Genital Warts

German Measles (Rubella)

Hepatitis

Influenza

Lassa Fever

Leukemia

Meningitis

Mumps

Polio

Rabies

Sexually Transmitted Diseases

Shingles

Warts

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Viral Biology

Virology is the discipline of microbiology that is concerned with the study of viruses. Knowledge of the basics of viral biology, viral reproduction (viral replication), and the ability to identify potential virus-related pathologies are increasingly important skills for some forensic scientists. There are a number of different viruses that challenge the human immune system and that may produce disease in humans. Although virologists are the scientists most directly concerned with viral biology, with the rise of terrorism and global health issues such as the evolving H5N1 influenza (commonly called bird flu), forensic scientists now find that their work overlaps interests in epidemiology and/or national security.

Viruses are essentially nonliving repositories of nucleic acid that require the presence of a living prokaryotic cell (where DNA is present in the cytoplasm) or eukaryotic cell (where DNA is present within the nucleus) for the replication of the nucleic acid. They can exist in a variety of hosts. Viruses can infect animals (including humans), plants, fungi, birds, aquatic organisms, protozoa, bacteria, and insects. Some viruses are able to infect several of these hosts, while other viruses are exclusive to one host.

Viral replication refers to the means by which virus particles make new copies of themselves. All viruses share the need for a host in order to replicate their deoxyribonucleic acid (DNA) or ribonucleic acid (RNA). The virus commandeers the host's existing molecules for the nucleic acid replication process. There are a number of different viruses. The differences include the disease symptoms they cause, their antigenic composition, type of nucleic acid residing in the virus particle, the way the nucleic acid is arranged, the shape of the virus, and the fate of the replicated DNA. These differences are used to classify the viruses and have often been the basis on which the various types of viruses were named.

The classification of viruses operates by use of the same structure that governs the classification of bacteria . The International Committee on Taxonomy of Viruses established the viral classification scheme in 1966. From the broadest to the narrowest level of classification, the viral scheme is: Order, Family, Subfamily, Genus, Species, and Strain/type. To use an example, the virus that was responsible for an outbreak of Ebola hemorrhagic fever in a region of Africa called Kikwit is classified as Order Mononegavirales, Family Filoviridae, Genus Filovirus, and Species Ebola Zaire.

In the viral classification scheme, all families end in the suffix viridae, for example Picornaviridae. Genera have the suffix virus. In the family Picornaviridae there are five genera: enterovirus, cardiovirus, rhinovirus, apthovirus, and hepatovirus. The names of the genera typically derive from the preferred location of the virus in the body (for those viral genera that infect humans). As examples, rhinovirus is localized in the nasal and throat passages, and hepatovirus is localized in the liver. Finally, within each genera there can be several species.

As noted above, there are a number of criteria by which members of one grouping of viruses can be distinguished from those in another group. For the purposes of classification, however, three criteria are paramount. These criteria are the host organism or organisms that the virus utilizes, the shape of the virus particle, and the type and arrangement of the viral nucleic acid.

An important means of classifying viruses concerns the type and arrangement of nucleic acid in the virus particle. Some viruses have two strands of DNA, analogous to the double helix of DNA that is present in prokaryotes such as bacteria and in eukaryotic cells. Some viruses, such as the Adenoviruses, replicate in the nucleus of the host using the replication machinery of the host. Other viruses, such as the Poxviruses, do not integrate in the host genome, but replicate in the cytoplasm of the host. Another example of a double-stranded DNA virus is the Herpesviruses. Other viruses only have a single strand of DNA such as the Parvoviruses, which can replicate their DNA in the host's nucleus. The replication involves the formation of what is termed as a negative-sense strand of DNA, a blueprint for the subsequent formation of the RNA and DNA used to manufacture the new virus particles.

The genome of other viruses, such as Reoviruses and Birnaviruses, is comprised of double-stranded RNA. Portions of the RNA function independently in the production of a number of so-called messenger RNAs, each of which produces a protein that is used in the production of new viruses. Other viruses contain a single strand of RNA. In some of the single-stranded RNA viruses, such as Picornaviruses, Togaviruses, and the Hepatitis A virus, the RNA is read in a direction that is termed "+ sense." The sense strand is used to make the protein products that form the new virus particles. Other single-stranded RNA viruses contain what is termed a negative-sense strand. Examples are the Orthomyxoviruses and the Rhabdoviruses. The negative strand is the blueprint for the formation of the messenger RNAs that are required for production of the various viral proteins.

Still another group of viruses have + sense RNA that contains the code for a DNA intermediate. The intermediate is used to manufacture the RNA that is eventually packaged into the new virus particles. The main example is the Retroviruses (the Human Immunodeficiency Viruses belong here). Finally, a group of viruses consist of double-stranded DNA that contains the code for an RNA intermediate. An example is the Hepadnaviruses.

One aspect of virology is the identification of viruses. Often, the diagnosis of a viral illness relies, at least initially, on the visual detection of the virus. Samples are prepared for electron microscopy using a technique called negative staining, which highlights surface detail of the virus particles. For this analysis, the shape of the virus is an important feature.

Any particular virus will have an attached shape. For example, viruses that specifically infect bacteria, the so-called bacteriophages, look similar to the Apollo lunar-landing spacecraft. A head region containing the nucleic acid is supported on a number of spider-like legs. Upon encountering a suitable bacterial surface, the virus acts like a syringe, to introduce the nucleic acid into the cytoplasm of the bacterium.

Other viruses have different shapes. These include spheres, ovals, worm-like forms, and even pleomorphic (irregular) arrangements. Some viruses, such as the influenza virus, have projections sticking out from the surface of the virus. These are crucial to the infectious process. As new species of eukaryotic and prokaryotic organisms are discovered, no doubt the list of viral species will continue to grow.

Viruses cannot replicate by themselves. They require the participation of the replication equipment of the host cell that they infect in order to replicate. The molecular means by which this replication takes place varies, depending upon the type of virus. Viral replication can be divided into three phases: initiation, replication, and release.

The initiation phase occurs when the virus particle attaches to the surface of the host cell, penetrates into the cell, and undergoes a process known as uncoating, where the viral genetic material is released from the virus into the host cell's cytoplasm. The attachment typically involves the recognition of some host surface molecules by a corresponding molecule on the surface of the virus. These two molecules can associate tightly with one another, binding the virus particle to the surface. A well-studied example is the haemagglutinin receptor of the influenzae virus. The receptors of many other viruses have also been characterized.

A virus particle may have more than one receptor molecule, to permit the recognition of different host molecules, or of different regions of a single host molecule. The molecules on the host surface that are recognized tend to be those that are known as glycoproteins. For example, the human immunodeficiency virus recognizes a host glycoprotein called CD4. Cells lacking CD4 cannot, for example, bind the HIV particle.

In the replication, or synthetic, phase the viral genetic material is converted to deoxyribonucleic acid (DNA) if the material originally present in the viral particle is ribonucleic acid (RNA). This so-called reverse transcription process needs to occur in retroviruses, such as HIV. The DNA is imported into the host nucleus where the production of new DNA, RNA, and protein can occur. The replication phase varies greatly from virus type to virus type. However, in general, proteins are manufactured to ensure that: the cell's replication machinery is harnessed to permit replication of the viral genetic material; the replication of the genetic material does indeed occur; and the newly made material is properly packaged into new virus particles.

Replication of the viral material can be a complicated process, with different stretches of the genetic material being transcribed simultaneously with some of these gene products required for the transcription of other viral genes. Also, replication can occur along a straight stretch of DNA, or when the DNA is circular (the so-called "rolling circle" form). RNA-containing viruses must also undergo a reverse transcription from DNA to RNA prior to packaging of the genetic material into the new virus particles.

In the final stage, the viral particles are assembled and exit the host cell. The assembly process can involve helper proteins, made by the virus or the host.

Release of viruses can occur by a process called budding. A membrane "bleb" containing the virus particle is formed at the surface of the cell and is pinched off. For herpes virus this is in fact how the viral membrane is acquired. In other words, the viral membrane is a host-derived membrane. Other viruses, such as bacteriophage, may burst the host cell, spewing out the many progeny virus particles. But many viruses do not adopt such a host destructive process, as it limits the time of an infection due to destruction of the host cells needed for future replication.

Although precise mechanisms vary, viruses cause disease by infecting a host cell and commandeering the host cell's synthetic capabilities to produce more viruses. The newly made viruses then leave the host cell, sometimes killing it in the process, and proceed to infect other cells within the host. Because viruses invade cells, drug therapies have not yet been designed to kill viruses, although some have been developed to inhibit their growth. The human immune system is the main defense against a viral disease.

Bacterial viruses, called bacteriophages, infect a variety of bacteria, such as Escherichia coli, a bacteria commonly found in the human digestive tract. Animal viruses cause a variety of fatal diseases. Acquired immune deficiency syndrome (AIDS) is caused by the human immunodeficiency virus (HIV); hepatitis and rabies are viral diseases; and hemorrhagic fevers, which are characterized by severe internal bleeding, are caused by filoviruses. Other animal viruses cause some of the most common human diseases. Often, these diseases strike in childhood. Measles, mumps, and chickenpox are viral diseases. The common cold and influenza are also caused by viruses. Finally, some viruses can cause cancer and tumors. One such virus, human T-cell leukemia virus (HTLV), was only recently discovered and its role in the development of a particular kind of leukemia is still being clarified.

Edward Jenner (17491823) is credited with developing the first successful vaccine against a viral disease, with his vaccine for smallpox . A vaccine works by eliciting an immune response. During this immune response, specific immune cells, called memory cells, are produced that remain in the body long after the foreign microbe present in a vaccine has been destroyed. When the body again encounters the same kind of microbe, the memory cells quickly destroy the microbe. Vaccines contain either a live, altered version of a virus or bacteria, or they contain only parts of a virus or bacteria, enough to elicit an immune response.

In 1797, Jenner developed his smallpox vaccine by taking infected material from a cowpox lesion on the hand of a milkmaid. Cowpox was a common disease of the era, transmitted through contact with an infected cow. Unlike smallpox, however, cowpox is a much milder disease. Using the cowpox pus, he inoculated an eight-year-old boy. Jenner continued his vaccination efforts through his lifetime. Until 1976, children were routinely vaccinated with the smallpox vaccine, called vaccinia. Reactions to the introduction of the vaccine ranged from a mild fever to severe complications, including (although very rarely) death. In 1977, when the last naturally occurring case of smallpox appeared and the global eradication of smallpox was complete, vaccinia vaccinations for children were discontinued, although vaccinia continues to be used as a carrier for recombinant DNA techniques. In these techniques, foreign DNA is inserted in cells. Efforts to produce a vaccine for HIV, for instance, have used vaccinia as the vehicle that carries specific parts of HIV.

see also Bacterial biology; Careers in forensic science; Ebola virus; Pathogens; Vaccines; Variola virus.

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Viral genetics

Viral genetics, the study of the genetic mechanisms that operate during the life cycle of viruses, utilizes biophysical, biological, and genetic analyses to study the viral genome and its variation. The virus genome consists of only one type of nucleic acid , which could be a single or double stranded DNA or RNA. Single stranded RNA viruses could contain positive-sense (+RNA), which serves directly as mRNA or negative-sense RNA (-RNA) that must use an RNA polymerase to synthesize a complementary positive strand to serve as mRNA. Viruses are obligate parasites that are completely dependant on the host cell for the replication and transcription of their genomes as well as the translation of the mRNA transcripts into proteins . Viral proteins usually have a structural function, making up a shell around the genome, but may contain some enzymes that are necessary for the virus replication and life cycle in the host cell. Both bacterial virus (bacteriophages) and animal viruses play an important role as tools in molecular and cellular biology research.

Viruses are classified in two families depending on whether they have RNA or DNA genomes and whether these genomes are double or single stranded. Further subdivision into types takes into account whether the genome consists of a single RNA molecule or many molecules as in the case of segmented viruses. Four types of bacteriophages are widely used in biochemical and genetic research. These are the T phages, the temperate phages typified by bacteriophage lambda, the small DNA phages like M13, and the RNA phages. Animal viruses are subdivided in many classes and types. Class I viruses contain a single molecule of double stranded DNA and are exemplified by adenovirus, simian virus 40 (SV40), herpes viruses, and human papillomaviruses. Class II viruses are also called parvoviruses and are made of single stranded DNA that is copied in to double stranded DNA before transcription in the host cell. Class III viruses are double stranded RNA viruses that have segmented genomes which means that they contain 10-12 separate double stranded RNA molecules. The negative strands serve as template for mRNA synthesis. Class IV viruses, typified by poliovirus, have single plus strand genomic RNA that serves as the mRNA. Class V viruses contain a single negative strand RNA which serves as the template for the production of mRNA by specific virus enzymes. Class VI viruses are also known as retroviruses and contain double stranded RNA genome. These viruses have an enzyme called reverse transcriptase that can both copy minus strand DNA from genomic RNA catalyze the synthesis of a complementary plus DNA strand. The resulting double stranded DNA is integrated in the host chromosome and is transcribed by the host's own machinery. The resulting transcripts are either used to synthesize proteins or produce new viral particles. These new viruses are released by budding, usually without killing the host cell. Both HIV and HTLV viruses belong to this class of viruses.

Virus genetics is studied by either investigating genome mutations or exchange of genetic material during the life cycle of the virus. The frequency and types of genetic variations in the virus are influenced by the nature of the viral genome and its structure. Especially important are the type of the nucleic acid that influence the potential for the viral genome to integrate in the host, and the segmentation that influence exchange of genetic information through assortment and recombination.

Mutations in the virus genome could either occur spontaneously or be induced by physical and chemical means. Spontaneous mutations that arise naturally as a result of viral replication are either due to a defect in the genome replication machinery or to the incorporation of an analogous base instead of the normal one. Induced virus mutants are obtained by either using chemical mutants like nitrous oxide that acts directly on bases and modify them or by incorporating already modified bases in the virus genome by adding these bases as substrates during virus replication. Physical agents such as ultra-violet light and x rays can also be used in inducing mutations. Genotypically, the induced mutations are usually point mutations, deletions, and rarely insertions. The phenotype of the induced mutants is usually varied. Some mutants are conditional lethal mutants. These could differ from the wild type virus by being sensitive to high or low temperature . A low temperature mutant would for example grow at 88°F (31°C) but not at 100°F (38°C), while the wild type will grow at both temperatures. A mutant could also be obtained that grows better at elevated temperatures than the wild type virus. These mutants are called hot mutants and may be more dangerous for the host because fever, which usually slows the growth of wild type virus, is ineffective in controlling them. Other mutants that are usually generated are those that show drug resistance, enzyme deficiency or an altered pathogenicity or host range. Some of these mutants cause milder symptoms compared to the parental virulent virus and usually have potential in vaccine development as exemplified by some types of influenza vaccines.

Besides mutation , new genetic variants of viruses also arise through exchange of genetic material by recombination and reassortment. Classical recombination involves breaking of covalent bonds within the virus nucleic acid and exchange of some DNA segments followed by rejoining of the DNA break. This type of recombination is almost exclusively reserved to DNA viruses and retroviruses. RNA viruses that do not have a DNA phase rarely use this mechanism. Recombination usually enables a virus to pick up genetic material from similar viruses and even from unrelated viruses and the eukaryotic host cells. Exchange of genetic material with the host is especially common with retroviruses. Reassortment is a non-classical kind of recombination that occurs if two variants of a segmented virus infect the same cell. The resulting progeny virions may get some segments from one parent and some from the other. All known segmented viruses that infect humans are RNA viruses. The process of reassortment is very efficient in the exchange of genetic material and is used in the generation of viral vaccines especially in the case of influenza live vaccines. The ability of viruses to exchange genetic information through recombination is the basis for virus-based vectors in recombinant DNA technology and hold great promises in the development of gene therapy . Viruses are attractive as vectors in gene therapy because they can be targeted to specific tissues in the organs that the virus usually infect and because viruses do not need special chemical reagents called transfectants that are used to target a plasmid vector to the genome of the host.

Genetic variants generated through mutations, recombination or reassortment could interact with each other if they infected the same host cell and prevent the appearance of any phen of any phenotype. This phenomenon, where each mutant provides the missing function of the other while both are still genotypically mutant, is known as complementation. It is used as an efficient tool to determine if mutations are in a unique or in different genes and to reveal the minimum number of genes affecting a function. Temperature sensitive mutants that have the same mutation in the same gene will for example not be able to complement each other. It is important to distinguish complementation reactivation where a higher dose of inactivated mutants will be reactivated and infect a cell because these inactivated viruses cooperate in a poorly understood process. This reactivation probably involves both a complementation step that allows defective viruses to replicate and a recombination step resulting in new genotypes and sometimes regeneration of the wild type. The viruses that need complementation to achieve an infectious cycle are usually referred to as defective mutants and the complementing virus is the helper virus. In some cases, the defective virus may interfere with and reduce the infectivity of the helper virus by competing with it for some factors that are involved in the viral life cycle. These defective viruses called "defective interfering" are sometimes involved in modulating natural infections. Different wild type viruses that infect the same cell may exchange coat components without any exchange of genetic material. This phenomenon, known as phenotypic mixing is usually restricted to related viruses and may change both the morphology of the packaged virus and the tropism or tissue specificity of these infectious agents.

See also Archaeogenetics; Epidemiology; Genetic engineering; Genetic identification of microorganisms; Immunology; Medical genetics; Mendelian genetics; Microbial genetics; Molecular biology; Organelles and subcellular genetics.


Resources

books

Beurton, Peter, Raphael Falk, and Hans-Jörg Rheinberger., eds. The Concept of the Gene in Development and Evolution. Cambridge, UK: Cambridge University Press, 2000.

Coffin, J.M., S.H. Hughes, and H.E. Varmus. Retroviruses. Cold Spring Harbor, NY: Cold Spring Harbor Press, 1997.

Flint, S.J., et al. Principles of Virology: Molecular Biology,Pathogenesis, and Control. Washington: American Society for Microbiology, 1999.

Lodish, H., et al. Molecular Cell Biology. 4th ed. New York: W. H. Freeman & Co., 2000.

Richman, D.D., and R.J. Whitley. Clinical Virology. 2nd ed. Washington: American Society for Microbiology, 2002.

periodicals

Buchschacher, G.L., Jr. "Introduction to Retroviruses and Retroviral Vectors." Somatic Cell and Molecular Genetics no. 26 (1-6) (November 2001) :1-11.

Bonhoeffer S., P. Sniegowski. "Virus Evolution: the Importance of Being Erroneous." Nature, 28, no. 420 (6914) (November 2002): 367, 369.


Abdel Hakim Nasr

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VIRUSES

Viruses are computer programs, usually malicious but occasionally unintentional, that spread through networks replicating themselves on shared programs and corrupting the computers in their path. While viruses have existed for years, they have taken on a new prominence and danger in the Internet Age, when they can spread much faster and compromise moreand more importantsystems. A vast industry arose to combat viruses, but it was largely engaged in an arms race in the early 2000s, as viruses continued to proliferate and mutate, growing more powerful and damaging.

Since computers and networking have become such a central component of economic and social activity, virus attacks, even relatively minor ones, have the potential to severely disrupt daily life. Out of that growing recognition, governments, corporations, and organizations, were coordinating efforts to prepare for and respond to computer viruses.

In a 2001 report titled Virus Prevalence Survey, the Reston, Virginia-based Internet security assurance firm ICSA.net reported that the number of companies that experienced major virus-related disasters increased more than 20 percent in 2000, while 40 percent of companies reported data losses from virus attacks. The report also noted that a typical company spent between $100,000 and $1 million on virus disasters and protection each year, and that figure was rising.

ICSA reported that the prevalence of virus attacks has increased from about 10 per 10,000 computers in 1996 to 91 per 10,000 in 2000, and analysts warned that the proportion would rise in the early 2000s. To make matters worse, each generation of viruses grows more sophisticated. In the early 2000s, virus hunters were challenged by new breeds of self-replicating and mutating viruses that change shape as they spread so as to avoid detection. Virus programmers increasingly incorporate encryption schemes into the programs so as to shield the source code, and metamorphic viruses include a mutation engine in their algorithms that enable them to alter slightly at each replication.

HOW VIRUSES WORK

To perform its function, a virus need only be able to replicate itself. Once a virus infects a computerby e-mail, disk, or some other methodthe program to which the virus is attached only has to be executed to trigger the virus into action. On top of mere replication, viruses may include a malicious payload, a mark that invites the user to perform an operation, such as opening an e-mail attachment. For example, the tag "I LOVE YOU" in the worm virus of the same name in 2000 constituted that virus's payload.

Viruses work in a variety of ways to disrupt a system, but the most common method was to simply overburden it by repeating the same messages over and over via rapid self-replications, eventually crashing the system. In addition, a computer virus may not take effect immediately. It can sit undetected in computer systems for months waiting for the right operation to trigger it into action. By that time, it may be quite difficult to retrace the steps of how a virus was lodged in a system to begin with.

TYPES OF VIRUSES

File infectors target data and executable files on a system's hard drive, and spread primarily by attaching themselves to such files as they spread through a system that uses shared programs. Since executable files are far less likely to be shared over diskettes or e-mail than are data files, according to Security Management, file infectors don't tend to be as successful at spreading outside of local networks.

Boot-sector infectors (BSIs) attack the master boot record the computer taps to start up. BSIs are among the most difficult virus programs to write, according to Security Management, and their claim on the virus population was declining since they don't tend to proliferate over networks and are spread primarily by diskette rather than by e-mail. Modern networking technology, then, was phasing out BSIs, although by the early 2000s they still constituted a significant threat.

Macro viruses attach themselves to those programs that alleviate computer users from performing repetitive tasks, and have grown more prominent in an environment of sophisticated personal computers with many automated macros. Macros are also frequently attached to data files, thus speeding the spread of macro viruses.

Worms were a particular subset of viruses that distinguish themselves by replicating across networks without ever directly attaching themselves to a host program, although the most widely publicized worm viruses were spread as e-mail attachments. Generally, worms invade an individual's computer through e-mail, and then use that individual's e-mail address list to send themselves to others. Worms are characterized by the speed with which they spread through systems; several major worms, such as Melissa and LoveLetter, spread globally before anti-virus players had even detected the problem, much less devised a disinfection program.

Trojan horses, as the Homeric name implies, distinguish themselves by deceit. They appear to the user as benign or beneficial, but insteador in additionperform unwanted and potentially destructive functions. Some Trojan horses directly attack files or programs, while others compromise security measures, most commonly by stealing passwords. Still other Trojan horses do no damage at all, but pretend to. These are joke or hoax programs that deceive the user into believing an infection has occurred.

FENDING OFF VIRUSES

By the early 2000s, virus attacks, or threats thereof, were so frequent that businesses were hard pressed to be prepared in advance for all potential attacks. Since predicting when or how a virus would occur was nearly impossible, most businesses, governments, and organizations devoted their efforts to detection, containment, and disinfection programs.

Scores of antivirus vendors specialize in software designed to detect incoming viruses and deflect them from their targets. Since viruses are constantly evolving, so are the programs designed to thwart them, and many organizations, particularly IT-intensive businesses, must make frequent online trips to those vendors' sites to acquire the latest virus patches and other updates. Once these fortifications are acquired, IT security personnel must allocate all the updates to their proper locations, which can be a tedious and time-consuming process.

Antivirus programs typically work by scanning all incoming information for known viruses by seeking out virus "signatures," or tell-tale signs of previously detected viruses. Such signatures generally include known programming patterns and codes, as well as more overt characteristics such as file names or types of e-mail attachments. But by its nature, this method forces antivirus vendors to continually play catch-up with viruses, and vendors are judged not only by the success of their products in fortifying systems against viruses, but also by how proactive they are in anticipating new virus strains. At any rate, IT security staffs are compelled to continually download the latest signature updates. With dozens of vendors issuing such updates, the task of regularly allocating the fortifications to their proper locations was increasingly costly, provoking many analysts to begin calling for more effective and user-friendly methods.

To make such tasks more manageable, antivirus vendors increasingly designed products for the server level, rather than the computer level. Not only were server-level virus screens easier to implement, they were increasingly practical as viruses were spread over server-based vehicles like e-mail. In addition, this provided multiple layers of security so that if an antivirus program failed to stop a virus at one level, it might still be thwarted at another level.

The emerging generation of antivirus programs may render obsolete the daunting task of updating signatures at the desktop level. Increasingly sophisticated programs were aimed at identifying and thwarting viruses based not on comparing their characteristics to lists of previous viruses, but by seeking out malicious behavior. This would be a huge step in the virus-antivirus arms race, allowing antivirus vendors to stop playing catch-up with virus programmers.

One obstacle to virus detection and eradication, according to some analysts, was the propensity of firms to keep internal virus damage quiet so as to avoid compromise of their stock prices or to otherwise try to circumvent financial or competitive disadvantage. While such practices can save a business from short-term headaches, it could also prove an obstacle to broader virus response techniques, since information sharing is so essential in order to get a handle on viruses.

FURTHER READING:

Greiner, Lynn. "IT's Battleground: The Quest for Virus Protection." Computing Canada, August 4, 2000.

Harley, David. "Living with Viruses." Security Management, August 2000.

Messmer, Ellen. "Experts Predict More Mutating Viruses." Network World, October 30, 2000.

Montana, John C. "Viruses and the Law: Why the Law is Ineffective." Information Management Journal, October 2000.

Nevin, Tom. "Computer VirusKnow the Enemy." African Business, April 2001.

Rash, Wayne. "What To Do When The Usual Security Steps Aren't Enough." InternetWeek, August 20, 2001.

Scheier, Robert L. "Managing the Virus Threat." Computer-world, May 7, 2001.

Trembly, Ara C. "The 10 Most Unwanted: 2001's Most Popular Viruses." National Underwriter, August 20, 2001.

"Viruses Rise, Criminals Walk, Public Confidence Falls." Security, February 2001.

SEE ALSO: Computer Crime; Denial of Service Attack; National Information Infrastructure Protection Act of 1996; National Infrastructure Protection Center; Computer Security; Worms

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Viral Genetics

Resources

Viral genetics is the study of the genetic mechanisms that operate during the various steps involved in the replication of virus. The study of viral genetics utilizes biophysical, biological, and genetic analyses to study the viral genome and its variation.

The virus genome consists of only one type of nucleic acid, which, depending on the virus, can be a single or double stranded form of deoxyribonucleic acid (DNA) or ribonucleic acid (RNA). Single stranded RNA viruses can contain what is termed positive-sense (+RNA), which serves directly as the template to make a molecule called messenger RNA (mRNA) that is in turn used to make protein. Other single strand virusescontain what is termed negative-sense RNA (-RNA); this form of genetic material requires the presence of an enzyme called RNA polymerase, which makes a complementary positive strand to serve as the template for mRNA.

Viral genetics is absolutely dependent on the genetic machinery of the host cell it infects, since viruses cannot replicate themselves alone. They require a host cell to replicate. Put another way, viruses are obligate parasites that are completely dependant on the host cell for the replication and transcription of their genomes as well as the translation of the mRNA transcripts into proteins. Viral proteins that are produced usually have a structural function, making up a shell around the genome, but may contain some enzymes that are necessary for the virus replication and life cycle in the host cell. Both bacterial virus (bacteriophages) and animal viruses play an important role as tools in molecular and cellular biology research.

Viruses are classified in two families depending on whether they have RNA or DNA genomes and whether these genomes are double or single stranded. Further subdivision into types takes into account whether the genome consists of a single RNA molecule or many molecules as in the case of viruses that are termed segmented viruses.

A great deal of what has been learned about viral genetics has come from the study of bacteriophages; viruses that specifically infect a target bacterial species. For example, coliphages specifically infect Escherichia coli. Other examples of well-studied viruses include the temperate (T) phages that are typified by bacteriophage lambda, small DNA phages such as M13, and the RNA phages. Animal viruses are subdivided in many classes and types. Class I viruses contain a single molecule of double stranded DNA and are exemplified by adenovirus, simian virus 40 (SV40), herpes viruses, and human papillomaviruses. Class II viruses are also called parvoviruses and are made of single stranded DNA that is copied in to double stranded DNA before transcription in the host cell. Class III viruses are double stranded RNA viruses that have segmented genomes which means that they contain 10-12 separate double stranded RNA molecules. Class IV viruses, typified by polio-virus, have a plus strand genomic RNA that serves as the mRNA. Class V viruses contain a single negative strand RNA. Class VI viruses are also known as retro-viruses and contain double stranded RNA genome. These viruses have an enzyme called reverse transcriptase that can both copy minus strand DNA from genomic RNA catalyze the synthesis of a complementary plus DNA strand. The resulting double stranded DNA is integrated in the host chromosome and is transcribed by the hosts own machinery. The resulting transcripts are either used to synthesize proteins or produce new viral particles. These new viruses are released by budding, usually without killing the host cell. The human immundeficiency virus (HIV) and human T cell leukemia virus (HTLV) are retroviruses.

Virus genetics mechanisms are studied by either investigating genome mutations or exchange of genetic material during the life cycle of the virus. The frequency and types of genetic variations in the virus are influenced by the nature of the viral genome and its structure. Especially important are the type of the nucleic acid that influence the potential for the viral genome to integrate in the host, and the segmentation that influence exchange of genetic information through assortment and recombination.

Mutations in the virus genome could either occur spontaneously or be induced by physical and chemical means. Spontaneous mutations that arise naturally as a result of viral replication are either due to a defect in the genome replication machinery or to the incorporation of an analogous base instead of the normal one. Induced virus mutants are obtained by either using chemical mutants like nitrous oxide that acts directly on bases and modify them or by incorporating already modified bases in the virus genome by adding these bases as substrates during virus replication. Physical agents such as ultra-violet light and x-rays can also be used in inducing mutations. Genotypically, the induced mutations are usually point mutations, deletions, and rarely insertions.

The phenotype of the induced mutants is usually varied. Some mutants are conditional lethal mutants. These could differ from the wild type virus by being sensitive to high or low temperature. A low temperature mutant would for example grow at 88° F (31° C), but not at 100° F (38° C), while the wild type will grow at both temperatures. A mutant could also be obtained that grows better at elevated temperatures than the wild type virus. These mutants are called hot mutants and may be more dangerous for the host because fever, which usually slows the growth of wild type virus, is ineffective in controlling them. Other mutants that are usually generated are those that show drug resistance, enzyme deficiency or an altered pathogenicity or host range. Some of these mutants cause milder symptoms compared to the parental virulent virus and usually have potential in vaccine development as exemplified by some types of influenza vaccines.

Besides mutation, new genetic variants of viruses also arise through exchange of genetic material by recombination and reassortment. Classical recombination involves breaking of covalent bonds within the virus nucleic acid and exchange of some DNA segments followed by rejoining of the DNA break. This type of recombination is almost exclusively reserved to DNA viruses and retroviruses. RNA viruses that do not have a DNA phase rarely use this mechanism. Recombination usually enables a virus to pick up genetic material from similar viruses and even from unrelated viruses and the eukaryotic host cells. Exchange of genetic material with the host is especially common with retroviruses. Reassortment is a non-classical kind of recombination that occurs if two variants of a segmented virus infect the same cell. The resulting progeny virions may get some segments from one parent and some from the other. All known segmented viruses that infect humans are RNA viruses. The process of reassortment is very efficient in the exchange of genetic material and is used in the generation of viral vaccines especially in the case of influenza live vaccines.

The ability of viruses to exchange genetic information through recombination is the basis for virus-based vectors in recombinant DNA technology and hold great promises in the development of gene therapy. Viruses are attractive as vectors in gene therapy because they can be targeted to specific tissues in the organs that the virus usually infect and because viruses do not need special chemical reagents called transfectants that are used to target a plasmid vector to the genome of the host.

Genetic variants generated through mutations, recombination or reassortment could interact with each other if they infected the same host cell and prevent the appearance of any phenotype. This phenomenon, where each mutant provides the missing function of the other while both are still genotypically mutant, is known as complementation. It is used as an efficient tool to determine if mutations are in a unique or in different genes and to reveal the minimum number of genes affecting a function. Temperature sensitive mutants that have the same mutation in the same gene will for example not be able to complement each other.

It is important to distinguish complementation from multiplicity reactivation where a higher dose of inactivated mutants will be reactivated and infect a cell because these inactivated viruses cooperate in a poorly understood process. This reactivation probably involves both a complementation step that allows defective viruses to replicate and a recombination step resulting in new genotypes and sometimes regeneration of the wild type. The viruses that need complementation to achieve an infectious cycle are usually referred to as defective mutants and the complementing virus is the helper virus. In some cases, the defective virus may interfere with and reduce the infectivity of the helper virus by competing with it for some factors that are involved in the viral life cycle. These defective viruses called defective interfering are sometimes involved in modulating natural infections. Different wild type viruses that infect the same cell may exchange coat components without any exchange of genetic material. This phenomenon, known as phenotypic mixing is usually restricted to related viruses and may change both the morphology of the packaged virus and the tropism or tissue specificity of these infectious agents.

Resources

BOOKS

Cann, Alan J. Principles of Molecular Virology. 4th ed. New York: Academic Press, 2005.

Ptashne, Mark. Genetic Switch: Phage Lambda Revisited. Cold Spring Harbor: Cold Spring Harbor Laboratory Press, 2004.

Richman, D.D., and R.J. Whitley. Clinical Virology. 2nd ed. Washington: American Society for Microbiology, 2002.

Wagner, Edward K. and Martinez J. Hewlett. Basic Virology. Boston: Blackwell Publishers, 2003.

PERIODICALS

Bonhoeffer S, P. Sniegowski. Virus evolution: the importance of being erroneous. Nature. 28;420 (6914) (Nov. 2002):367-369.

Abdel Hakim Nasr

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Viral genetics

Viral genetics, the study of the genetic mechanisms that operate during the life cycle of viruses , utilizes biophysical, biological, and genetic analyses to study the viral genome and its variation. The virus genome consists of only one type of nucleic acid, which could be a single or double stranded DNA or RNA . Single stranded RNA viruses could contain positive-sense (+RNA), which serves directly as mRNA or negative-sense RNA (RNA) that must use an RNA polymerase to synthesize a complementary positive strand to serve as mRNA. Viruses are obligate parasites that are completely dependant on the host cell for the replication and transcription of their genomes as well as the translation of the mRNA transcripts into proteins. Viral proteins usually have a structural function, making up a shell around the genome, but may contain some enzymes that are necessary for the virus replication and life cycle in the host cell. Both bacterial virus (bacteriophages) and animal viruses play an important role as tools in molecular and cellular biology research.

Viruses are classified in two families depending on whether they have RNA or DNA genomes and whether these genomes are double or single stranded. Further subdivision into types takes into account whether the genome consists of a single RNA molecule or many molecules as in the case of segmented viruses. Four types of bacteriophages are widely used in biochemical and genetic research. These are the T phages, the temperate phages typified by bacteriophage lambda, the small DNA phages like M13, and the RNA phages. Animal viruses are subdivided in many classes and types. Class I viruses contain a single molecule of double stranded DNA and are exemplified by adenovirus, simian virus 40 (SV40), herpes viruses and human papilloma viruses. Class II viruses are also called parvoviruses and are made of single stranded DNA that is copied in to double stranded DNA before transcription in the host cell. Class III viruses are double stranded RNA viruses that have segmented genomes which means that they contain 1012 separate double stranded RNA molecules. The negative strands serve as template for mRNA synthesis. Class IV viruses, typified by poliovirus, have single plus strand genomic RNA that serves as the mRNA. Class V viruses contain a single negative strand RNA which serves as the template for the production of mRNA by specific virus enzymes. Class VI viruses are also known as retroviruses and contain double stranded RNA genome. These viruses have an enzyme called reverse transcriptase that can both copy minus strand DNA from genomic RNA catalyze the synthesis of a complementary plus DNA strand. The resulting double stranded DNA is integrated in the host chromosome and is transcribed by the host own machinery. The resulting transcripts are either used to synthesize proteins or produce new viral particles. These new viruses are released by budding, usually without killing the host cell. Both HIV and HTLV viruses belong to this class of viruses.

Virus genetics are studied by either investigating genome mutations or exchange of genetic material during the life cycle of the virus. The frequency and types of genetic variations in the virus are influenced by the nature of the viral genome and its structure. Especially important are the type of the nucleic acid that influence the potential for the viral genome to integrate in the host, and the segmentation that influence exchange of genetic information through assortment and recombination .

Mutations in the virus genome could either occur spontaneously or be induced by physical and chemical means. Spontaneous mutations that arise naturally as a result of viral replication are either due to a defect in the genome replication machinery or to the incorporation of an analogous base instead of the normal one. Induced virus mutants are obtained by either using chemical mutants like nitrous oxide that acts directly on bases and modify them or by incorporating already modified bases in the virus genome by adding these bases as substrates during virus replication. Physical agents such as ultra-violet light and x rays can also be used in inducing mutations. Genotypically, the induced mutations are usually point mutations, deletions, and rarely insertions. The phenotype of the induced mutants is usually varied. Some mutants are conditional lethal mutants. These could differ from the wild type virus by being sensitive to high or low temperature. A low temperature mutant would for example grow at 88°F (31°C) but not at 100°F (38°C), while the wild type will grow at both temperatures. A mutant could also be obtained that grows better at elevated temperatures than the wild type virus. These mutants are called hot mutants and may be more dangerous for the host because fever, which usually slows the growth of wild type virus, is ineffective in controlling them. Other mutants that are usually generated are those that show drug resistance, enzyme deficiency, or an altered pathogenicity or host range. Some of these mutants cause milder symptoms compared to the parental virulent virus and usually have potential in vaccine development as exemplified by some types of influenza vaccines.

Besides mutation, new genetic variants of viruses also arise through exchange of genetic material by recombination and reassortment. Classical recombination involves the breaking of covalent bonds within the virus nucleic acid and exchange of some DNA segments followed by rejoining of the DNA break. This type of recombination is almost exclusively reserved to DNA viruses and retroviruses. RNA viruses that do not have a DNA phase rarely use this mechanism. Recombination usually enables a virus to pick up genetic material from similar viruses and even from unrelated viruses and the eukaryotic host cells. Exchange of genetic material with the host is especially common with retroviruses. Reassortment is a non-classical kind of recombination that occurs if two variants of a segmented virus infect the same cell. The resulting progeny virions may get some segments from one parent and some from the other. All known segmented virus that infect humans are RNA viruses. The process of reassortment is very efficient in the exchange of genetic material and is used in the generation of viral vaccines especially in the case of influenza live vaccines. The ability of viruses to exchange genetic information through recombination is the basis for virus-based vectors in recombinant DNA technology and hold great promises in the development of gene therapy. Viruses are attractive as vectors in gene therapy because they can be targeted to specific tissues in the organs that the virus usually infect and because viruses do not need special chemical reagents called transfectants that are used to target a plasmid vector to the genome of the host.

Genetic variants generated through mutations, recombination or reassortment could interact with each other if they infected the same host cell and prevent the appearance of any phenotype . This phenomenon, where each mutant provide the missing function of the other while both are still genotypically mutant, is known as complementation. It is used as an efficient tool to determine if mutations are in unique or in different genes and to reveal the minimum number of genes affecting a function. Temperature sensitive mutants that have the same mutation in the same gene will for example not be able to complement each other. It is important to distinguish complementation from multiplicity reactivation where a higher dose of inactivated mutants will be reactivated and infect a cell because these inactivated viruses cooperate in a poorly understood process. This reactivation probably involves both a complementation step that allows defective viruses to replicate and a recombination step resulting in new genotypes and sometimes regeneration of the wild type. The viruses that need complementation to achieve an infectious cycle are usually referred to as defective mutants and the complementing virus is the helper virus. In some cases, the defective virus may interfere with and reduce the infectivity of the helper virus by competing with it for some factors that are involved in the viral life cycle. These defective viruses called "defective interfering" are sometimes involved in modulating natural infections. Different wild type viruses that infect the same cell may exchange coat components without any exchange of genetic material. This phenomenon, known as phenotypic mixing is usually restricted to related viruses and may change both the morphology of the packaged virus and the tropism or tissue specificity of these infectious agents.

See also Viral vectors in gene therapy; Virology; Virus replication; Viruses and responses to viral infection

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Epidemics, viral

An epidemic is an outbreak of a disease that involves a large number of people in a contained area (e.g., village, city, country). An epidemic that is worldwide in scope is referred to as a pandemic. A number of viruses have been responsible for epidemics . Some of these have been present since antiquity, while others have emerged only recently.

Smallpox is an example of an ancient viral epidemic. Outbreaks of smallpox were described in 1122 B.C. in China. In A.D. 165, Roman Legionnaires returning from military conquests in Asia and Africa spread the virus to Europe. One third of Europe's population died of smallpox during the 15-year epidemic. Smallpox remained a scourge until the late eighteenth century. Then, Edward Jenner devised a vaccine for the smallpox virus, based on the use of infected material from cowpox lesions. Less than a century later, naturally occurring smallpox epidemics had been ended.

Influenza is an example of a viral epidemic that also has its origins in ancient history. In contrast to smallpox, influenza epidemics remain a part of life today, even with the sophisticated medical care and vaccine development programs that can be brought to bear on infections.

Epidemics of influenza occurred in Europe during the Middle Ages. By the fifteenth century, epidemics began with regularity. A devastating epidemic swept through Spain, France, the Netherlands, and the British Isles in 14261427. Major outbreaks occurred in 1510, 1557, and 1580. In the eighteenth century there were three to five epidemics in Europe. Three more epidemics occurred in the nineteenth century. Another worldwide epidemic began in Europe in 1918. American soldiers returning home after World War I brought the virus to North America. In the United States alone almost 200,000 people died. The influenza epidemic of 1918 ranks as one of the worst natural disasters in history. In order to put the effects of the epidemic into perspective, the loss of life due to the four years of conflict of World War I was 10 million. The death toll from influenza during 5 months of the 1918 epidemic was 20 million.

Epidemics of influenza continue to occur. Examples include epidemics of the Asian flu (1957), and the Hong Kong flu (1968). Potential epidemics due to the emergence of new forms of the virus in 1976 (the Swine flu) and 1977 (Russian flu) failed to materialize.

The continuing series of influenza epidemics is due to the ability of the various types of the influenza virus to alter the protein composition of their outer surface. Thus, the antibodies that result from an influenza epidemic in one year may be inadequate against the immunologically distinct influenza virus that occurs just a few years later. Advances in vaccine design and the use of agents that lessen the spread of the virus are contributing to a decreased scope of epidemics. Still, the threat of large scale influenza epidemics remains.

In the twentieth century, new viral epidemics have emerged. A number of different viruses have been grouped together under the designation of hemorrhagic fevers . These viruses are extremely contagious and sweep rapidly through the affected population. A hallmark of such infections is the copious internal bleeding that results from the viral destruction of host tissue. Death frequently occurs. The high death rate in fact limits the scope of these epidemics. Essentially the virus runs out of hosts to infect. The origin of hemorrhagic viruses such as the Ebola virus is unclear. A developing consensus is that the virus periodically crosses the species barrier from its natural pool in primates.

Another viral epidemic associated with the latter half of the twentieth century is acquired immunodeficiency syndrome. This debilitating and destructive disease of the immune system is almost certainly caused by several types of a virus referred to as the Human Immunodeficiency Virus (HIV ). The first known death due to HIV infection was a man in the Congo in 1959. The virus was detected in the United States only in 1981. Subsequent examination of stored blood sample dating back 40 years earlier revealed the presence of HIV.

HIV may have arisen in Africa, either from a previously unknown virus, or by the mutation of a virus resident in a non-human population (e.g., primates). The tendency of the virus to establish a latent infection in the human host before the appearance of the symptoms of an active infection make it difficult to pinpoint the origin of the virus. Moreover, this aspect of latency, combined with the ready ability of man to travel the globe, contributes to the spread of the epidemic. Indeed, the epidemic may now be more accurately considered to be a pandemic.

A final example of a twentieth century viral epidemic is that caused by the Hanta virus. The virus causes a respiratory malady that can swiftly overwhelm and kill the patient. The virus is normally resident on certain species of mouse. In the mid-1990s, an epidemic of Hanta virus syndrome occurred in native populations in the Arizona and New Mexico areas of the United States west. As with other viral epidemics, the epidemic faded away as quickly as it had emerged. However, exposure of someone to the mouse host or to dried material containing the virus particles can just as quickly fuel another epidemic.

Given their history, it seems unlikely viral epidemics will be eliminated. While certain types of viral agents will be defeated, mainly by the development of effective vaccines and the undertaking of a worldwide vaccination program (e.g., smallpox), other viral diseases will continue to plague mankind.

See also AIDS; Hemorrhagic fevers and diseases; Virology

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Viruses

Viruses are infectious agents that have no organelles or reproductive machinery of their own. Viruses cannot duplicate their DNA or RNA, nor can they translate their genetic information into protein. Essentially, they are small bags of genes that typically encode a comparatively small number of proteins. For example, the human immunodeficiency virus (HIV) is composed of only nine genes, yet with these simple nine bits of protein it can wreak havoc on the human immune system. Others, such as herpes simplex or adenovirus, can have large genomes with dozens of genes. Simple or complex, though, all viruses have the same function. As they cannot make protein or reproduce on their own, viruses must force bacteria or animal cells to do their work for them. A virus is, simply put, a genetic parasite.

As it does not have to sustain other energetically expensive cellular processes, a virus has a very simple structure. It is usually composed of nucleic acids (DNA or RNA) and a protein coat. This coat may be a very primitive covering (called a capsid) or it may be a complex structure derived from a host's membrane (called an envelope). Viral envelopes may possess a variety of receptors and decoys designed to fool the host's immune system. Avoiding detection is one of a virus's main tasks, and viruses may rely on dummy surface molecules or manipulating the immune system to do so. For example, HIV convinces infected cells to stop producing molecular flags that indicate infection to the rest of the body. In order to be successful, a virus must defeat the immune system and reproduce itself efficiently.

A viral life cycle generally has five distinct phases:

  1. Attachment: The virus must connect itself to the target cell. Often, this is accomplished by molecules on the virus that mimic cell surface receptors required to interact with other cells. Rhinoviruses, some of which cause the common cold, bind to intercellular adhesion molecules (ICAMs) on the respiratory tract. ICAMs are meant to help white blood cells find their targets, but rhinoviruses have evolved to use them to get into cells. HIV binds to CD4 and CCR5, two surface markers involved in T-cell trafficking. Such binding may restrict the virus to infecting certain species or certain types of cells within a species.
  2. Penetration: Once docked, the virus must get its nucleic material inside the cell. Some viruses are taken entirely into the cell. Others inject their DNA or RNA through the cell membrane. Still others fuse their membrane with their hosts' and dump the nuclear contents into the cytosol. In order for the virus to use the host's reproduction capabilities, it needs to be inside the cell.
  3. Replication: Once the nucleic acids are inside, the virus will use the host's replication machinery to make more copies of itself. Some viruses, such as HIV, are made of RNA instead of DNA. For this reason, these viruses must first transcribe their genomes into DNA in order for cells to copy them. Whether made of DNA or RNA, though, a virus will also force the host cell to make its protein coat and any other proteins necessary to put the virus together. Rather than expending its precious energy on maintenance, the host cell instead is forced to use its energy to make viral parts.
  4. Assembly: The various parts of the virus are put together with its freshly copied DNA. Soon the host cell is full of these virions, or individual viral particles, and the virions are ready to infect another cell.
  5. Lysis: The virus ruptures the cell and disperses its viral progeny, all off to infect new host cells and begin the cycle again.

Not all viruses lyse (rupture) their host cells. Some may bud off the host cell. Others may become latent and rest in the host's cytosol or even the host's own chromosomes for a long time without causing damage. For example, herpes simplex 1 infects individuals and causes cold sores, but does so only intermittently. Cytomegalovirus (CMV) and Epstein-Barr virus (EBV), also known as mononucleosis, both infect the human body and remain latent for life. These viruses are held in check by the immune system and cause no harm, but they never go away completely. Persons with acquired immune deficiency syndrome (AIDS) lose immune function, and CMV and EBV have been known to resurface in persons with AIDS.

Because some viruses insert themselves into the host's genome, there is a possibility that they might affect normal gene regulation in the host itself. Viruses can be responsible for certain cellular problems that involve gene regulation. For example, some viruses are thought to be the cause of certain types of cancer. Human papilloma virus, for example, has been associated with cervical cancer. Hepatitis B and hepatitis C cause a majority of the world's cases of liver cancer.

While viruses can be specific for a particular species, cross-species infection happens frequently and sometimes with disastrous results. For example, all fifteen known strains of influenza A virus reside in aquatic birds, preferring the intestinal tracts of ducks in particular. As such, fowl fecal matter, as well as seals, whales, pigs, horses, and chickens, have been implicated in a number of human influenza outbreaks.

As a parasite, the best evolutionary strategy for a virus is for it not to harm the host. It is thought that HIV-1 and HIV-2 were introduced to humanity through the ingestion of uncooked monkeys (a chimpanzee and a sooty mangabey, respectively) sometime in the early twentieth century. These monkeys had been infected with simian immunodeficiency virus (SIV), which is fairly benign to its host. In species such as the mangabeys, African green monkeys, and pigtailed macaques, SIV causes no detectable problems and infection is widespread (it is estimated that some 80 percent of captive sooty mangabeys carry the disease). Infected rhesus monkeys, however, lose their ability to fight disease and waste away. Likewise, when the virus mutated to HIV in humans, it infected human populations and continues to cause widespread sickness and death. If HIV is to be with humanity for a long time, then it must become a little less virulent, lest it kill off all of its hosts.

see also Animal Testing.

Ian Quigley

Bibliography

Cann, Alan J., ed. DNA Virus Replication. New York: Oxford University Press, 2000.

Dalgleish, Angus, and Robin Weiss. HIV and the New Virus. San Diego: Academic, 1999.

Johnson, George B. Biology: Visualizing Life. New York: Holt, Rinehart and Winston, Inc., 1998.