Retroviruses

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Retroviruses

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.

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

Infectious Diseases: In Context