A. Genera

The Retroviridae family is divided into seven genera: Alpharetrovirus (which contains avian leukosis and sarcoma viruses), Betaretrovirus (mouse mammary tumor virus), Gammaretro virus (mammalian leukemia and sarcoma viruses), Deltaretrovirus (human T-lymphotropic viruses [HTLV] and bovine leukemia virus), Epsilonretrovirus (fish viruses), Spumavirus (which contains viruses able to cause “foamy” degeneration of inoculated cells but which are not associated with any known disease process), and Lentivirus (which encompasses agents able to cause chronic infections with slowly progressive neurologic impairment, including HIV.

Retroviruses can be organized in various ways depending on their morphologic, biologic, and genetic properties. Differences in genome sequences and natural host range are frequently used, but antigenic properties are not. Retroviruses may be grouped morphologically (types B, C, and D); the vast majority of isolates display type C characteristics.

B. Host of Origin

Retroviruses have been isolated from virtually all vertebrate species. Natural infections by a given virus are usually limited to a single species, though 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.

C. 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 whether (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 may affect cellular gene expression patterns. 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.

D. Host Range

The presence or absence of an appropriate cell surface recep tor 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 cultured cells from the natural host. Many endogenous viruses have xenotropic host ranges.

E. Genetic Content

Retroviruses have a simple genetic content, but there is some variation in the number and type of genes contained. The genetic makeup of a virus influences its biologic proper ties. Genomic structure is a useful way of categorizing RNA tumor viruses (Figure 2).

Fig1.Genetic organization of representative retroviruses. A: Nondefective, replication-competent viruses. Examples of retroviruses with simple and complex genomes are shown. An open rectangle shows the open reading frame for the indicated gene. If the rectangles are offset vertically, their reading frames are different. Horizontal lines connecting two rectangles indicate that this segment is spliced out. Simple genomes: ALV, avian leukosis virus (Alpharetrovirus); MLV, murine leukemia virus (Gammaretrovirus); MMTV, mouse mammary tumor virus (Betaretrovirus). Complex genomes: HIV, human immunodeficiency virus type 1 (Lentivirus); HTLV, human T-lymphotropic virus (Deltaretrovirus). B: Viruses carrying oncogenes. Several examples are shown, with the oncogene shaded; all are defective except RSV. Ab-MLV, Abelson murine leukemia virus (abl oncogene) (Gammaretrovirus); Ha-MSV, Harvey murine sarcoma virus (ras oncogene) (Gammaretrovirus); MC29, avian myelocytomatosis virus (myc oncogene) (Alpharetrovirus); Mo-MSV, Moloney murine sarcoma virus (mos oncogene) (Gammaretrovirus); RSV, Rous sarcoma virus (src oncogene) (Alpharetrovirus). The scale for genome sizes is shown at the bottom of each panel. (Modified with permission from Vogt VM: Retroviral virions and genomes. In Coffin JM, Hughes SH, Varmus HE [editors]. Retroviruses. Cold Spring Harbor Laboratory Press, 1997.)

Such viruses are highly oncogenic in appropriate host animals and can transform cells in culture. With very few exceptions, the addition of the cellular DNA results in the loss of portions of the viral genome. Consequently, the sarcoma viruses usually are replication-defective; progeny virus is produced only in the presence of helper viruses. The helper viruses are generally other retroviruses (leukemia viruses), which may recombine in various ways with the defective viruses. These defective transforming retroviruses have been the source of many of the recognized cellular oncogenes.

F. Oncogenic Potential

The retroviruses that contain oncogenes are highly oncogenic. They are sometimes referred to as “acute trans forming” 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 slow-transforming leukemia viruses, the viral promoter or enhancer element is inserted adjacent to or near the cellular gene in the cellular chromosome.

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مواضيع ذات صلة

Replication of Retroviruses

Interactions of Tumor Viruses with Their Hosts

PAPILLOMAVIRUSES

General Features of Viral Carcinogenesis

Immunity and Prevention of Rabies Virus

Methods of Antiviral Susceptibility Testing: Influenza

Methods of Antiviral Susceptibility Testing: Genotypic Susceptibility Assays

Methods of Antiviral Susceptibility Testing: Phenotypic Assays

Pathogenesis and Pathology of Rabies Virus

Properties of the Rabies Virus

Coronavirus Infections in Humans

Properties of Coronaviruses