RETROVIRUSES

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Structure & Composition. Retrovirus particles contain the helical ribonucleoprotein within an icosahedral capsid that is surrounded by an outer membrane (envelope) containing glycoprotein and lipid. Type-specific or subgroup-specific antigens are associated with the glycoproteins in the viral envelope, which are encoded by the env gene; group-specific antigens are associated with the virion core, which are encoded by the gag gene. The retrovirus genome consists of two identical subunits of single-stranded, positive-sense RNA, each 7–11 kb in size. The reverse transcriptase contained in virus particles is essential for viral replicatio

Host of Origin. Retroviruses have been isolated from virtually all vertebrate species. Most viruses of a given type are isolated from a single species, though natural infections across species barriers may occur. Group-specific antigenic determinants on the major internal (core) protein are shared by viruses from the same host species. All mammalian viruses are more closely related to one another than to those from avian species.

The RNA tumor viruses most widely studied experimentally are the sarcoma viruses of chickens and mice and the leukemia viruses of mice, cats, chickens, and humans.

Exogenous or Endogenous. Exogenous retroviruses are spread horizontally and behave as typical infectious agents. They initiate infection and transformation only after contact. In contrast to endogenous viruses, which are found in all cells of all individuals of a given species, gene sequences of exogenous viruses are found only in infected cells. The pathogenic retroviruses all appear to be exogenous viruses.

Retroviruses may also be transmitted vertically through the germ line. Viral genetic information that is a constant part of the genetic constitution of an organism is designated as "endogenous." An integrated retroviral provirus behaves like a cluster of cellular genes and is subject to regulatory control by the cell. This cellular control usually results in partial or complete repression of viral gene expression. Its location in the cellular genome and the presence of appropriate cellular transcription factors determine to a great extent if (and when) viral expression will be activated. It is not uncommon for normal cells to maintain the endogenous viral infection in a quiescent form for extended periods of time.

Many vertebrates, including humans, possess multiple copies of endogenous RNA viral sequences. The endogenous viral sequences are of no apparent benefit to the animal. However, it has recently been discovered that endogenous proviruses of mammary tumor virus carried by inbred strains of mice express superantigen activities that influence the T cell repertoires of the animals.

Endogenous viruses are usually not pathogenic for their host animals. They do not produce any disease and cannot transform cells in culture. (There are examples of disease caused by replication of endogenous viruses in inbred strains of mice.)

Important features of endogenous viruses are as follows: (1) DNA copies of RNA tumor virus genomes are covalently linked to cellular DNA and are present in all somatic and germ cells in the host; (2) endogenous viral genomes are transmitted genetically from parent to offspring; (3) the integrated state subjects the endogenous viral genomes to host genetic control; and (4) the endogenous virus may be induced to replicate either spontaneously or by treatment with extrinsic (chemical) factors.

Host Range. The presence or absence of an appropriate cell surface receptor is a major determinant of the host range of a retrovirus. Infection is initiated by an interaction between the viral envelope glycoprotein and a cell surface receptor. Ecotropic viruses infect and replicate only in cells from animals of the original host species. Amphotropic viruses exhibit a broad host range (able to infect cells not only of the natural host but of heterologous species as well) because they recognize a receptor that is widely distributed. Xenotropic viruses can replicate in some heterologous (foreign) cells but not in cells of the natural host. Many endogenous viruses have xenotropic host ranges.

Oncogenic Potential. The retroviruses that contain oncogenes are highly oncogenic. They are sometimes referred to as "acute transforming" agents because they induce tumors in vivo after very short latent periods and rapidly induce morphologic transformation of cells in vitro. The viruses that do not carry an oncogene have a much lower oncogenic potential. Disease (usually of blood cells) appears after a long latent period (ie, "slow transforming"); cultured cells are not transformed.

Briefly, neoplastic transformation by retroviruses is the result of a cellular gene that is normally expressed at low, carefully regulated levels becoming activated and expressed constitutively. In the case of the acute transforming viruses, a cellular gene has been inserted by recombination into the viral genome and is expressed as a viral gene under the control of the viral promoter. In the case of the leukemia viruses, the viral promoter or enhancer element is inserted adjacent to or near the cellular gene in the cellular chromosome.

Human Retroviruses. Only a few retroviruses are linked to human tumors. The human T-lymphotropic (HTLV) group of retroviruses has probably existed in humans for thousands of years. HTLV-1 has been established as the causative agent of adult T cell leukemia-lymphomas (ATL) as well as a nervous system degenerative disorder called tropical spastic paraparesis. It does not carry an oncogene. A related human virus, HTLV-2, has been isolated but has not been conclusively associated with a specific disease. HTLV-1 and HTLV-2 share about 65% sequence homology and display significant serologic cross-reactivity.

The virus is distributed worldwide, with an estimated 10 to 20 million infected individuals. Clusters of HTLV-associated disease are found in certain geographic areas (southern Japan, Melanesia, the Caribbean, Central and South America, and parts of Africa).

Transmission of HTLV-1 seems to involve cell-associated virus. Mother-to-child transmission via breast feeding is an important mode. Efficiency of transmission from infected mother to child is estimated at 15–25%. Such early-life infections are associated with the greatest risk of ATL. Blood transfusion is an effective means of transmission, as are sharing blood-contaminated needles (drug abusers) and sexual intercourse.

About 1-3% of infected individuals will develop aggressive leukemia after an incubation period which is usually several decades long. Following an asymptomatic period, the patient may progress to chronic/smouldering ATL. This is manifested by skin lesions and high leukocyte count. They then progress to acute ATL within several months. Symptoms include lymphadenopathy, hepatosplenomegaly, and hypercalcaemia. The survival time is measured in months.

Mechanism of transformation. The human lymphotropic viruses have a marked affinity for mature T cells.

Retroviruses can induce the transformed state within the cells they infect by two mechanisms. Both of these mechanisms are related to the life cycle of these viruses. When a retrovirus infects a cell its RNA genome is converted into DNA by the viral encoded RNA-dependent DNA polymerase (reverse transcriptase). The DNA then integrates into the genome of the host cell where it can remain being copied as the host genome is duplicated during the process of cellular division. The long terminal repeats (LTRs) promote the transcription of the viral DNA leading to the production of new virus particles. It appears that the viral promoter-enhancer sequences in LTRs may be responsive to signals associated with the activation and proliferation of T cells. If so, the replication of the viruses may be linked to the replication of the host cells—a strategy that would ensure efficient propagation of the virus.

The human retroviruses are transregulating. They carry a gene, tax, that is necessary for viral replication and may contribute to oncogenesis by also modulating cellular genes that regulate cell growth and promoting cell proliferation.

At some frequency the integration process leads to rearrangement of the viral genome and the consequent incorporation of a portion of the host genome into the viral genome. This process is termed transduction. Occasionally this transduction process leads to the virus acquiring a proto-oncogene from the host that is normally involved in cellular growth control. Because of the alteration of the host proto-oncogene during the transduction process as well as the gene being transcribed at a higher rate due to its association with the retroviral LTRs the transduced oncogene confers a growth advantage to the infected cell. The end result of this process is unrestricted cellular proliferation leading to tumorigenesis. Numerous oncogenes have been discovered in the genomes of transforming retroviruses.

The second mechanism by which retroviruses can transform cells relates to the powerful transcription promoting effect of the LTRs. When a retrovirus genome integrates into a host genome it does so randomly. At some frequency this integration process leads to the placement of the LTRs close to a gene that encodes a growth regulating protein. If the protein is expressed at an abnormally elevated level it can result in cellular transformation. This is termed retroviral integration induced transformation.