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Retroviruses

Retroviruses

Retroviruses are viruses in which the genetic material consists of ribonucleic acid (RNA ) instead of the usual deoxyribonucleic acid (DNA ). Retroviruses produce an enzyme known as reverse transcriptase that can transform RNA into DNA, which can then be permanently integrated into the DNA of the infected host cells.

Many gene therapy treatments and experiments use disabled mouse retroviruses as a carrier (vector) to inject new genes into the host DNA. Retroviruses are rendered safe by adding, mutating, or deleting viral genes so that the virus cannot reproduce after acting as a vector for the intended delivery of new genes. Although viruses are not normally affected by antibiotics , genes can be added to retroviruses that make them susceptible to specific antibiotics.

As of 2002, researchers have discovered only a handful of retroviruses that infect humans. Human immunodeficiency virus (HIV ), the virus that causes acquired immune deficiency syndrome (AIDS ), is a retrovirus. Another human retrovirus, human T-cell leukemia virus (HTLV ), was discovered three years prior to the discovery of HIV. Both HTLV and HIV attack human immune cells called T cells . T cells are the linchpin of the human immune response. When T cells are infected by these retroviruses, the immune system is disabled and several serious illnesses result. HTLV causes a fatal form of cancer called adult T cell leukemia. HTLV infection of T cells changes the way the T cells work in the body, causing cancer. HIV infection of T cells, however, eventually kills T cells, rendering the immune system powerless to stave off infections from microorganisms .

Retroviruses are sphere-shaped viruses that contain a single strand or a couple of strands of RNA. The sphere-shaped capsule of the virus consists of various proteins. The capsule is studded on the outside with proteins called receptor proteins. In HIV, these receptor proteins bind to special proteins on T cells called CD4 receptors. CD4 stands for cluster of differentiation, and CD type 4 is found on specific T cells called helper cells. The human retroviruses discovered so far bind only to CD4 receptors, which makes their affinity for T helper cells highly specific.

The retrovirus receptor docks with a CD4 receptor on a T cell, and enters the T cell through the T cell membrane. Once inside, the retrovirus begins to replicate. But because the retrovirus's genetic material consists of RNA, not DNA, replication is more complicated in a retrovirus than it is for a virus that contains DNA.

In all living things, DNA is the template by which RNA is transcribed. DNA is a double-stranded molecule that is located within the nucleus of cells. Within the nucleus, DNA transcribes RNA, a single-stranded nucleic acid. The RNA leaves the nucleus through tiny pores and enters the cytoplasm , where it directs the synthesis of proteins. This process has been called the "central dogma" of genetic transcription . No life form has been found that violates this central dogmaexcept retroviruses. In retroviruses, the RNA is used to transcribe DNA, which is exactly opposite to the way genetic material is transcribed in all other living things. This reversal is why they are named retrograde, or backwards, viruses.

In addition to RNA, retroviruses contain an enzyme called reverse transcriptase. This is the enzyme that allows the retrovirus to make a DNA copy from RNA. Once this DNA copy is made, the DNA inserts itself into the T cell's DNA. The inserted DNA then begins to produce large numbers of viral RNA that are identical to the infecting virus's RNA. This new RNA is then transcribed into the proteins that make up the infecting retrovirus. In effect, the T cell is transformed into a factory that produces more retroviruses. Because reverse transcriptase enzyme is unique to retroviruses, drugs that inhibit the action of this enzyme are used to treat retroviral infection, such as HIV. Reverse transcriptase is vital for retrovirus replication, but not for human cell replication. Therefore, modern reverse transcriptase inhibitor drugs are specific for retroviruses. Often, reverse transcriptase inhibitors are used in combination with other drugs to treat HIV infection.

Retroviruses are especially lethal to humans because they cause a permanent change in the T cell's DNA. Other viruses merely commandeer their host cell's cytoplasm and chemical resources to make more viruses; unlike retroviruses, they do not insert their DNA into the host cell's DNA. Nor do most viruses attack the body's T cells. Most people's cells, therefore, can recover from an attack from a virus. Eventually, the body's immune system discovers the infection and neutralizes the viruses that have been produced. Any cells that contain viruses are not permanently changed by the viral infection. Because retroviruses affect a permanent change within important cells of the immune system, cellular recovery from a retrovirus infection does not occur.

In 1980, researchers headed by Robert Gallo at the National Cancer Institute discovered the first human retrovirus. They found the virus within leukemic T cells of patients with an aggressive form of T cell cancer. These patients were from the southern United States, Japan, and the Caribbean. Almost all patients with this form of cancer were found to have antibodies (immune system proteins made in response to an infection) to HTLV.

HIV is perhaps the most famous retrovirus. Discovered independently by several researchers in 1983, HIV is now known to be the causative agent of AIDS. People with AIDS test positive for HIV antibodies, and the virus itself has been isolated from people with the disease.

HIV attacks T cells by docking with the CD4 receptor on its surface. Once inside the cell, HIV begins to transcribe its RNA into DNA, and the DNA is inserted into the T cell's DNA. However, new HIV is not released from the T cell right away. Instead, the virus stays latent within the cell, sometimes for 10 years or more. For reasons that are not yet clear, at some point the virus again becomes active within the T cell, and HIV particles are made within the cell. The new HIV particles bud out from the cell membrane and attack other T cells. Soon, all of the T cells of the body are infected and die. This infection cycle explains why very few virus particles are found in people with the HIV infection (those who do not yet have AIDS); many particles are found in people who have fulminate AIDS.

No cure has yet been found for AIDS. Researchers are still unsure about many aspects of HIV infection, and research into the immune system is still a relatively new science. Several anti-retroviral drugs, such as AZT, ddI, and ddC, have been administered to people with AIDS. These drugs do not cure HIV infection; but they usually postpone the development of AIDS. AIDS is almost invariably fatal.

Simian immunodeficiency virus (SIV) is the primate version of HIV. In fact, monkeys infected with SIV are used to test AIDS drugs for humans. Rous sarcoma virus (RSV) causes cancer in chickens and was the first retrovirus identified. Feline leukemia virus (FELV) causes feline leukemia in cats and is characterized by symptoms similar to AIDS. Feline leukemia is a serious disease that, like AIDS, is fatal. Unlike AIDS, a vaccine has been developed to prevent this disease.

See also AIDS, recent advances in research and treatment; Immunogenetics; T cells or T lymphocytes; Viral genetics; Viral vectors in gene therapy; Virus replication; Viruses and responses to viral infection

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Seroconversion

Seroconversion

Seroconversion is a term that refers to the development in the blood of antibodies to an infectious organism or agent. Typically, seroconversion is associated with infections caused by bacteria , viruses , and protozoans. But seroconversion also occurs after the deliberate inoculation with an antigen in the process of vaccination . In the case of infections, the development of detectable levels of antibodies can occur quickly, in the case of an active infection, or can be prolonged, in the case of a latent infection. Seroconversion typically heralds the development of the symptoms of the particular infection.

The phenomenon of seroconversion can be important in diagnosing infections that are caused by latent viruses. Examples of viruses include hepatitis B and C viruses, the Epstein Barr virus, and the Human Immunodeficiency Virus (HIV ). When these viruses first infect people, the viral nucleic acid can become incorporated into the genome of the host. As a result, there will not be an immune response mounted against the virus. However, once viral replication has commenced antibodies to viral proteins can accumulate to detectable levels in the serum.

Seroconversion is am important aspect of Acquired Immunodeficiency Syndrome (AIDS ). Antibodies to HIV can sometimes be detected shortly after infection with the virus, and before the virus becomes latent. Symptoms of infection at this stage are similar to the flu, and disappear quickly, so treatment is often not sought. If, however, diagnosis is made at this stage, based on presence of HIV antibodies, then treatment can begin immediately. This can be important to the future outlook of the patient, because often at this stage of the infection the immune system is relatively undamaged. If seroconversion occurs following activation of the latent virus, then immune destruction may already be advanced.

The presence of antibodies in the serum occurs much earlier in the case of infections that occur very soon after the introduction of the infectious microorganism. The type of antibody present can be used in the diagnosis of the infection. Additionally, seroconversion in the presence of symptoms but in the absence of detectable microorganisms (particularly bacteria) can be a hallmark of a chronic infection caused by the adherent bacterial populations known as biofilms. Again, the nature of the antibodies can help alert a physician to the presence of a hitherto undetected bacterial infection , and treatment can be started.

See also Antibiotic resistance, tests for; Antibody and antigen; Antibody-antigen, biochemical and molecular reactions; Antibody formation and kinetics; Immunity, active, passive and delayed; Immunochemistry; Immunodeficiency disease syndromes; Serology

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Retroviruses

Retroviruses

Introduction

History and Scientific Foundations

Applications and Research

Impacts and Issues

BIBLIOGRAPHY

Introduction

Retroviruses are viruses that contain ribonucleic acid (RNA) as their genetic material. This contrasts with the majority of other microorganisms that instead contain deoxyribonucleic acid (DNA). Like other viruses, retroviruses create new copies of themselves by infecting a host cell and using the hosts’ genetic replication machinery. To accomplish this, early in the infection process of retroviruses an enzyme called reverse transcriptase is produced. The enzyme can transform the viral RNA into DNA, which is then inserted into the host DNA. The inserted viral DNA can be replicated along with the host DNA during growth and division of the host cell, and the manufactured viral components assemble to form new copies of the virus.

Retroviruses cause a number of serious infections in humans and other creatures. The most infamous is acquired immunodeficiency syndrome (AIDS, also cited as acquired immune deficiency syndrome), which is considered by most scientists to be caused by several versions of a retrovirus called the human immunodeficiency virus (HIV). Other retroviruses can stimulate abnormal cell growth; these retroviruses can also be termed oncogenic viruses.

History and Scientific Foundations

The first known retrovirus, the Rous sarcoma virus, was discovered in 1911. It was subsequently shown that the virus was a cause of cancer in some species of chickens. The demonstration of the ability of retroviruses to cause human diseases did not come until almost 70 years later.

In 1980, researchers at the National Cancer Institute discovered the first human retrovirus. They found the virus within leukemic T cells of patients with an aggressive form of T cell cancer. These patients were from the southern United States, Japan, and the Caribbean. Almost all patients with this form of cancer were found to have antibodies (immune system proteins made in response to an infection) to HTLV.

HTLV and HIV infect and replicate inside of T cells, which are vital to the human immune response. As more T cells are disabled, the immune system becomes progressively less efficient and microorganisms not normally capable of causing disease are able to do so. These infections are called opportunistic infections. HTLV also causes a lethal cancer called adult T cell leukemia.

Retroviruses are spherical. An outer structure called a capsule surrounds either one or two strands of RNA. The capsule also contains proteins that can recognize target protein sites on the host cell. The association of the viral and host proteins enables the virus to attach to the host cell, which is necessary before the virus can enter the host. For example, in the case of the HIV retrovirus, the viral proteins bind to T cell proteins called CD4 receptors.

Once inside the host cell, the retrovirus begins to make more copies. Retroviruses are an exception to the general order of replication, which involves the use of DNA as a template to make a type of RNA called messenger RNA, which in turn provides the information to make proteins. Instead, retroviruses have a preliminary step in which the viral RNA is used to manufacture DNA. From then on, the replication process occurs as in other cells.

Retroviruses contain an enzyme called reverse transcriptase that produces DNA from the viral RNA. The viral-derived DNA can then be integrated into the host's DNA. When the host cell replicates, the viral DNA is read along with the host DNA. The manufactured viral components are then assembled to produce new virus particles. Reverse transcriptase is unique to retroviruses. This is their Achilles’ heel. Drugs that impair this enzyme can interrupt the production of new retrovirus. As a result, therapies to treat HIV infections usually include a reverse transcriptase inhibitor.

WORDS TO KNOW

DEOXYRIBONUCLEIC ACID (DNA): Deoxyribonucleic acid (DNA) is a double-stranded, helical molecule that forms the molecular basis for heredity in most organisms.

GENE THERAPY: Gene therapy is the name applied to the treatment of inherited diseases by corrective genetic engineering of the dysfunctional genes. It is part of a broader field called genetic medicine, which involves the screening, diagnosis, prevention, and treatment of hereditary conditions in humans. The results of genetic screening can pinpoint a potential problem to which gene therapy can sometimes offer a solution. Genetic defects are significant in the total field of medicine, with up to 15 out of every 100 newborn infants having a hereditary disorder of greater or lesser severity. More than 2000 genetically distinct inherited defects have been classified so far, including diabetes, cystic fibrosis, hemophilia, sickle-call anemia, phenylketonuria, Down syndrome and cancer.

HUMAN IMMUNODEFICIENCY VIRUS (HIV): The human immunodeficiency virus (HIV) belongs to a class of viruses known as the retroviruses. These viruses are known as RNA viruses because they have RNA (ribonucleic acid) as their basic genetic material instead of DNA (deoxyribonucleic acid).

HUMAN T-CELL LEUKEMIA VIRUS: Two types of human T-cell leukemia virus (HTLV) are known. They are also known as human T-cell lymphotrophic viruses. HTLV-1 often is carried by a person with no obvious symptoms. However, HTLV-I is capable of causing a number of maladies. These include abnormalities of the T cells and B cells, a chronic infection of the myelin covering of nerves that causes a degeneration of the nervous system, sores on the skin, and an inflammation of the inside of the eye. HTLV-II infection usually does not produce any symptoms. However, in some people a cancer of the blood known as hairy cell leukemia can develop.

ONCOGENIC VIRUS: An oncogenic virus is a virus that is capable of changing the cells it infects so that the cells begin to grow and divide uncontrollably.

OPPORTUNISTIC INFECTION: An opportunistic infection is so named because it occurs in people whose immune systems are diminished or are not functioning normally; such infections are opportunistic insofar as the infectious agents take advantage of their hosts’ compromised immune systems and invade to cause disease.

REVERSE TRANSCRIPTASE: An enzyme that makes it possible for a retrovirus to produce DNA (deoxyribonucleic acid) from RNA (ribonucleic acid).

RIBONUCLEIC ACID (RNA): Any of a group of nucleic acids that carry out several important tasks in the synthesis of proteins. Unlike DNA (deoxyribonucleic acid), it has only a single strand. Nucleic acids are complex molecules that contain a cell's genetic information and the instructions for carrying out cellular processes. In eukaryotic cells, the two nucleic acids, ribonucleic acid (RNA) and deoxyribonucleic acid (DNA), work together to direct protein synthesis. Although it is DNA (deoxyribonucleic acid) that contains the instructions for directing the synthesis of specific structural and enzymatic proteins, several types of RNA actually carry out the processes required to produce these proteins. These include messenger RNA (mRNA), ribosomal RNA (rRNA), and transfer RNA (tRNA). Further processing of the various RNAs is carried out by another type of RNA called small nuclear RNA (snRNA). The structure of RNA is very similar to that of DNA, however, instead of the base thymine, RNA co

ROUS SARCOMA VIRUS: Rous sarcoma virus, named after American doctor Francis Peyton Rous (1879–1970), is a virus that can cause cancer in some birds, including chickens. It was the first virus known go to be able to cause cancer.

T CELL: Immune-system white blood cells that enable antibody production, suppress antibody production, or kill other cells. When a vertebrate encounters substances that are capable of causing it harm, a protective system known as the immune system comes into play. This system is a network of many different organs that work together to recognize foreign substances and destroy them. The immune system can respond to the presence of a disease-causing agent (pathogen) in two ways. Immune cells called the B cells can produce soluble proteins (antibodies) that can accurately target and kill the pathogen. This branch of immunity is called humoral immunity. In cell-mediated immunity, immune cells known as the T cells produce special chemicals that can specifically isolate the pathogen and destroy it.

IN CONTEXT: SCIENTIFIC, POLITICAL, AND ETHICAL ISSUES

In 1980, a U.S. research team headed by Robert Gallo (1937–) reported their discovery of a retrovirus that caused cancer in humans. The virus was designated human T-cell leukemia virus (HTLV). Three years later, HIV was reported almost simultaneously in 1983 by two U.S. research teams (including Gallo's) and a French team. Because the researchers used different designations for the virus, a debate arose over which team was truly the first to discover HIV. The debate was heated, since the discovery was almost immediately recognized as extremely important and likely of Nobel Prize significance. In the end, in the spirit of scientific cooperation, the researchers put aside their debate and agreed to be co-discoverers.

Retroviruses that cause cancer do so when the reverse transcribed-viral DNA is integrated into the DNA of the host. In some cases, the viral DNA can insert itself within a gene. This will alter the sequence of the gene, which can, in turn, alter or completely destroy the genetic information. This sort of disruption may occur in a gene that codes for a molecule that helps regulate cell division. When this happens, the result can be the uncontrolled cell growth and division that is the hallmark of cancer.

Applications and Research

Retroviral research has focused on understanding how the viruses infect cells, with the aim of blocking or even preventing the infection. Blocking the attachment of the virus to the host cell by binding an added molecule either to the viral protein involved in binding or to the target site on the host surface can prevent infection. Within the human body, this sequence is not as straightforward as it is in the laboratory, but progress is being made.

A powerful potential application of retroviruses involves their use as vehicles to get genes inside of other cells. This technique has been explored in gene therapy, where host genes can be disrupted or their activity increased, depending on the aim of the therapy. When the retroviral genetic material enters the host cell and, in turn, enters the host DNA, the target gene is also inserted. This can allow the target gene to be expressed. In another approach, the insertion of the retrovirus can disrupt a host gene. For example, insertion of the viral genetic material can disable a bacterial gene that codes for the manufacture of a destructive toxin. However, as discussed below, the trials of retroviral gene therapy in humans have been plagued with problems.

Impacts and Issues

Retroviruses that cause human diseases sickened and killed millions of people in the twentieth century alone. While the best known of these diseases is AIDS, other retroviruses cause paralysis, physical and mental deterioration, at least one type of muscular dystrophy, multiple sclerosis, and arthritis.

Multiple sclerosis and arthritis are examples of autoimmune diseases, in which the body's immune system malfunctions and reacts against it own tissues. There is evidence that such autoimmune diseases may be caused by inserted retroviral genetic material. The original insertion, which produced the genetic changes that underlie the immune difficulties, may have occurred thousands of years ago, with the inserted DNA being passed from generation to generation ever since. Studies have shown that this ancient retroviral genetic material makes up almost 10 percent of the human genome.

Retroviral diseases are global and affect people in wealthy and poorer nations. The consequences are particularly severe in developing countries, since these diseases can disrupt family life (since care for the afflicted person is necessary), and cause absences from school and the workplace that impair the national economies.

Retroviruses that are used in gene therapy are altered to cripple their ability to establish an infection in host cells. These disabled retroviruses are able to incorporate their genetic material into the host cell genome, but are not able to produce new viruses. These retroviruses have been used in disease therapy in animals. But retroviral gene therapy in humans is still experimental.

In 1999, 18-year-old Jesse Gelsinger died of multiple organ failure days after beginning retroviral gene therapy. A severe immune reaction to the retrovirus used is argued to have been responsible for his death. In 2003, the U.S. Food and Drug Administration banned gene therapy trials using retroviruses in a type of cells called blood stem cells. The ban continues as of 2007.

See AlsoHIV; Pneumocystis carinii Pneumonia; Viral Disease.

BIBLIOGRAPHY

Books

Lyon, Maureen, and Lawrence J. D'Angelo. Teenagers, HIV, and AIDS: Insights from Youths Living with the Virus. Washington, DC: Praeger Publishers, 2006.

Mader, Sylvia. Biology. 8th ed. New York: McGraw-Hill, 2003.

Whiteside, Alan. HIV/AIDS: A Very Short Introduction. Oxford: Oxford University Press, 2007.

Brian Hoyle

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