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Transformation by Retroviruses
Two features of the replicative cycle of retroviruses are related to the oncogenic potential of this class of viruses. First, most retroviruses do not kill the host cell, but instead set up a permanent infection with continual virus production. Second, a DNA copy of the RNA genome is integrated into the host cell DNA by a virally encoded integrase (IN); however, unlike bacteriophage integration, a linear form of the viral DNA, rather than a circular form, is the substrate for integration. Furthermore, unlike , there does not appear to be a specific site in the cell DNA where integration occurs.
Retroviruses are known to transform cells by three different mechanisms. First, many animal retroviruses have acquired transforming genes called oncogenes. More than 30 such oncogenes have now been found since the original oncogene was identified in Rous sar-coma virus (called v-src, where the v stands for viral). Because normal cells possess hom-ologs of these genes called protooncogenes (eg, c-src, where c stands for cellular), it is generally thought that viral oncogenes originated from host DNA. It is possible they were picked up by “copy choice” recombination involving packaged cellular mRNAs as previ-ously described. Because these transforming viruses carry cellular genes, they are some-times referred to as transducing retroviruses. Most of the viral oncogenes have suffered one or more mutations that make them different from the cellular protooncogenes. These changes presumably alter the protein products so that they cause transformation. Although the mechanisms of oncogenesis are not completely understood, it appears that transforma-tion results from inappropriate production of an abnormal protein that interferes with nor-mal signaling processes within the cell. Uncontrolled cell proliferation is the result. Because tumor formation by retroviruses carrying an oncogene is efficient and rapid, these viruses are often referred to as acute transforming viruses. Although common in some animal species, this mechanism has not yet been recognized as a cause of any human cancers.
The second mechanism is called insertional mutagenesis and is not dependent on continued production of a viral gene product. Instead, the presence of the viral promoter or enhancer is sufficient to cause the inappropriate expression of a cellular gene residing in the immediate vicinity of the integrated provirus. This mechanism was first recognized in avian B-cell lymphomas caused by an avian leukosis virus, a disease characterized by a very long latent period. Tumor cells from different individuals were found to have a copy of the provirus integrated at the same place in the cellular DNA. The site of the provirus insertion was found to be next to a cellular protooncogene called c-myc. The myc gene had previously been identified as a viral oncogene called v-myc. In this case, transforma-tion occurs not because the c-myc gene is altered by mutation but because the viral pro-moter adjacent to the gene turns on its expression continuously and the gene product is overproduced. The disease has a long latent period; because, although the birds are viremic from early life, the probability of an integration occurring next to the c-myc gene is very low. Once such an integration event does occur, however, cell proliferation is rapid and a tumor develops. No human tumors are known for certain to result from insertional mutagenesis caused by a retrovirus; however, human cancers are known where a chromo-some translocation has placed an active cellular promoter next to a cellular protoonco-gene (Burkitt’s lymphoma and chronic myelogenous leukemia).
The third mechanism was revealed by the discovery of the first human retrovirus. The virus, human T-cell lymphotropic virus type 1 (HTLV-1), is the causative agent of adult T-cell leukemia. HTLV-1 sequences are found integrated in the DNA of the leukemic cells and all the tumor cells from a particular individual have the proviral DNA in the same location. This observation indicates that the tumor is a clone derived from a single cell; however, the sites of integration in tumors from different individuals are different. Thus, HTLV-1 does not cause malignancy by promoter insertion near a particular cellular gene. Instead, the virus has a gene called tax that codes for a protein that acts in trans (ie, on other genes in the same cell) to not only promote maximal transcription of the proviral DNA, but also to transcriptionally activate an array of cellular genes. The resulting cellu-lar proteins cooperate to cause uncontrolled cell proliferation. The tax gene is therefore different from the oncogenes of the acute transforming retroviruses in that it is a viral gene rather than a gene derived from a cellular protooncogene. HTLV-1 is commonly de-scribed as a transactivating retrovirus.
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