Retroviruses
Retroviruses are a class of RNA viruses that replicate by converting their RNA into DNA and integrating it into the host's genome. Members of the Retroviridae family, these viruses are enveloped and typically measure around 100 nanometers in diameter. They possess a unique life cycle that involves the use of an enzyme called reverse transcriptase to synthesize double-stranded DNA from their RNA genome. This DNA, once integrated into the host genome, is termed a "provirus" and can replicate along with the host's genetic material.
Some retroviruses are known to cause serious diseases, including certain types of cancer. They can inadvertently acquire genes from the host during infection, which may lead to oncogenic transformations over generations. Notable examples of retroviruses include the human immunodeficiency virus (HIV), which leads to AIDS, and the human T-cell leukemia virus (HTLV). The study of retroviruses has important implications in genetics and medicine, as modified retroviruses are utilized in gene therapy to correct genetic defects. However, the high mutation rates of retroviruses make developing effective treatments and vaccines particularly challenging.
Retroviruses
ANATOMY OR SYSTEM AFFECTED: All
DEFINITION: Ribonucleic acid (RNA) viruses that replicate by synthesizing a double-stranded deoxyribonucleic acid (DNA) molecule that integrates into the host genome. They are known to infect virtually all animals and sometimes cause serious diseases, including cancer.
Biology of Retroviruses
Retroviruses are members of the viral family Retroviridae. They are enveloped, positive-sense (+) RNA viruses about 100 nanometers in diameter that replicate within the host’s cytoplasm through a double-stranded DNA intermediate that is integrated into the host genome. In addition to the +RNA, there is a cellular transfer RNA (tRNA) hydrogen-bonded to the +RNA that serves as a primer for the enzyme reverse transcriptase.
The viral RNA genome and its associated nucleoprotein, reverse transcriptase, and integrase are surrounded by a protein capsid. Immediately external to the capsid is the matrix protein. The outer layer of the retrovirus is a lipid bilayer envelope derived from the host’s plasma membrane that is acquired as the virus emerges from the host cell. Within the envelope are two glycoproteins that are encoded by the virus genome and serve as plasma-membrane attachment sites during entry into the cell.
The retrovirus genome consists of two identical +RNA molecules, between seven and eleven kilobases in length, that code for only a few proteins, including gag, which codes for the matrix, capsid, and nucleoprotein; pol, which codes for reverse transcriptase, RNAse, integrase, and a protease; and env, which codes for the envelope glycoproteins.
The retrovirus binds to plasma-membrane receptors via the viral envelope glycoproteins. When the retrovirus enters the cell, the viral RNA is released along with its reverse transcriptase. A double-stranded DNA is synthesized from the +RNA using viral reverse transcriptase. Integrase catalyzes the incorporation of the double-stranded DNA molecule into the host genome. When integrated, the viral DNA is referred to as a "provirus" and replicates with the host genome. Host RNA polymerase transcribes the viral genes, making copies of the viral genome and mRNA molecules that can be translated into viral proteins. Viral RNA and proteins are assembled into new viral particles that emerge from the plasma membrane by budding.
Some retroviruses, such as Rous sarcoma virus (RSV), feline leukemia virus (FLV), and mouse mammary tumor virus (MMTV), can induce tumors in their host species. More than twenty-five cancer-causing (oncogenic) retroviruses have been isolated. A retrovirus gains oncogenic potential when it inadvertently acquires a eukaryotic gene during infection. Although the eukaryotic gene may not be oncogenic when first acquired, after several generations it may mutate or otherwise become altered, transforming it into one that is oncogenic. Retroviruses such as FLV that do not carry an oncogene can still transform by disrupting the function of a normal gene, either by integrating within it or by integrating next to it so that the neighboring gene can use the viral promoter, resulting in gene overexpression and cellular proliferation.
Perspective and Prospects
The study of retroviruses dates to 1910 with the work of Peyton Rous, who discovered that certain sarcomas in chickens were caused by an agent later identified as a virus. The virus was later named Rous sarcoma virus. In 1970, the laboratories of Howard Temin and David Baltimore independently discovered that certain RNA viruses have an enzyme, now known as reverse transcriptase, that permit the viruses to reverse transcribe their RNA genomes into double-stranded DNA. In the early 1970s, the laboratory of J. Michael Bishop and Harold Varmus demonstrated that Rous sarcoma virus has a gene, now known as src, responsible for transforming normal cells into tumor cells. Uninfected cells, including human cells, have a normal src gene that is related to the viral src gene. In the past, an RSV infected a chicken and incorporated the host src gene into its own genome. The src gene acquired by the virus became altered over time so that it now causes cancer when an RSV infects a chicken cell.
There are many examples of retroviruses, including human T-cell leukemia virus (HTLV), the first pathogenic human retrovirus, discovered in 1980 by Bernard J. Poiesz, Robert Gallo, and their colleagues at the National Institutes of Health (NIH) and by Mitsuaki Yoshida in Japan. Human immunodeficiency virus (HIV), which causes acquired immunodeficiency syndrome (AIDS), is also a retrovirus; it was discovered in 1983 by Luc Montagnier, Françoise Barré-Sinoussi, and their colleagues at the Pasteur Institute in France.
Since reverse transcriptase does not have the proofreading activities associated with DNA polymerase, retroviruses mutate and evolve more rapidly than DNA viruses, making the development of drugs and vaccines difficult.
Recombinant retroviruses are often used as vectors for genetic engineering. Retroviruses that are modified by removing the genes that make them harmful and replacing them with normal eukaryotic genes can be used to deliver a normal copy of a gene to a defective cell. The DNA copy of the recombinant retrovirus can integrate into the host genome and genetically modify the cell.
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