Genetic Factors in Viral Carcinogenesis

27 May

Host genes that regulate the expression of virus-induced leukemia in animals have been studied to a much greater extent than host genes involved in chemical and physical carcinogenesis (cf. Meruelo and Bach, 1983; Kozak et al., 1989). The susceptibility  of mice to the Friend virus (FV), a typical oncogenic RNA virus, has been shown to be the result of a multiple-gene trait (cf. Steeves and Lilly, 1977). In particular, a locus in the host’s genome termed the Fv-1 locus on chromosome 4 significantly affects the susceptibility of the host to the virus. The function of the gene product of the Fv-1 locus is not entirely clear. Recently, Best et al. (1996) have cloned the Fv-1 gene and demonstrated that it appears to be derived from the gag region of an endogenous retrovirus unrelated to murine leukemia viruses. Since genetic restriction at the Fv-1 locus re- sults in failure of the Friend murine leukemia virus DNA to integrate into the host genome (cf. Axelrad, 1989), Goff (1996) has pointed out that the Fv-1 gene product is able to block virus development during the early phase of the viral life cycle after reverse transcription but before establishment of the integrated provirus in the host genome. The site within the cell where the Fv-1 gene product acts is uncertain. At least two alleles of this locus occur, and one may sepa- rate mouse strains into two types (N type and B type) depending on which of the two alleles is present in their genome. It is possible to characterize viruses as N-tropic or B-tropic—that  is, whether the virus replicates in NIH (N-type) mice or in BALB/c (B-type) mice. Thus, the gene is quite important for the susceptibility of specific mouse strains to certain RNA oncogenic viruses.

Another genetic locus, the Fv-2 gene, has a major effect on the response of mice to the Friend and to the Rauscher murine retroviruses. Mice recessive for this gene are completely re- sistant to these viruses, whereas heterozygotes and homozygotes for the normal gene product are susceptible. Risser (1979) suggested that the Fv-2 locus codes for a specific hematopoietic dif- ferentiation antigen. More recently, Hoatlin et al. (1990) have presented evidence that the Fv-2 protein controls the response to a leukemogenic membrane glycoprotein (gp55) encoded by the Friend spleen focus-forming virus and the hormone erythropoietin. Through such regulatory ef- fects, the Fv-2 gene product can modulate infection by the virus in hematopoietic tissue.

As shown in Table 8.2, at least three other Fv genes have been described, each of which regulates different aspects of the expression of the Friend virus. A large number of other genetic loci associated with expression of viruses or viral products have also been described in various strains of mice. In strain AKR mice and their hybrids, loci coding for the endogenous form of the virus have been found within their genomes—that is, the Akv locus localized to chromosome

7. The nomenclature  for the latter locus has been changed to Emr-11 (Bedigian et al., 1983). Other examples of such structural genes for endogenous viruses within the genome of the host have been described in the BALB/c strain of mouse (Kozak and Rowe, 1979), as well as another locus on chromosome 1 in at least five different mouse strains (Kozak and Rowe, 1980).

Although these genes have been most carefully studied in the mouse, similar genes have also been described in other species including the Bvr-1 locus in the cat, which restricts the ex- pression of a type-C RNA virus (O’Brien, 1976) and the Bevi locus on human chromosome 6, which controls the replication of baboon type-C virus in human cells (Lemons et al., 1977).

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