Genetic determinants of neoplastic diseases induced by a subgroup F avian leukosis virus

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EU-8 is a recombinant avian leukosis virus (ALV) constructed in vitro, which carries long terminal repeats and gag and pol genes from ring-necked pheasant virus and the env gene from UR2AV. Unlike either parent virus, when injected into 10-day-old chicken embryos, EU-8 induces a high incidence of clonally arising B-cell lymphomas within an unusually short latent period, often causing death within 5 to 7 weeks after infection. These tumors differ from the classic lymphoid leukosis induced by ALV in several respects, both biologically and at the molecular level. Most notably, in all of the EU-8-induced tumors examined, the provirus was integrated in the c-myb locus, and in no tumors were c-myc integrations found. Most of the proviral integrations were downstream of the initiation codon of c-myb and thus presumably resulted in some truncation of the c-myb gene product, although not to the same extent as has been found in other cases of c-myb activation. In addition, several of the proviruses were integrated well upstream of the c-myb coding region. This is the first report of ALV interaction with the c-myb proto-oncogene and the first report of c-myb activation resulting in tumors of lymphoid rather than myeloid origin, suggesting that the target cell specificity of transformation by the myb gene is not as restricted as previously believed. Retroviruses have traditionally been divided into two classes: acute and nonacute. The acute retroviruses carry transforming genes derived from host proto-oncogenes. They cause neoplastic disease with a high incidence, often approaching 100%, and a short latent period of days to weeks. The nonacute retroviruses lack oncogenes and induce neoplasia with a much longer latency, typically 4 to 12 months. Tumors caused by nonacute retroviruses are generally clonal and are thought to result from proviral integration into or adjacent to cellular proto-oncogenes. Avian leukosis viruses (ALVs), which fall into the latter category of retroviruses, induce a variety of neoplastic diseases in birds, including lymnphoma, nephroblastoma, fibrosarcoma, and erythroblastosis (3, 7, 58). The neoplasm most commonly induced by most strains of ALV is a B-cell lymphoma, which originates in the bursa of Fabricius (35, 40). The vast majority of these tumors contain proviral insertions in the c-myc locus (16, 23, 38). ALVs can be classified into subgroups on the basis of host range properties conferred by their envelope glycoprotein (env) genes. Ring-n8cked pheasant virus (RPV), a subgroup-F ALV, has the unusual property of inducing rapidly appearing lung angiosarcomas when injected into 10-day-old chicken embryos (7). The angiosarcomas are not clonal and show no evidence of proto-oncogene activation by proviral insertion (52). In previous studies, the genetic determinant responsible for the induction of lung tumors was localized to the env gene of RPV (52). This was done by constructing recombinants between RPV and UR2AV, a subgroup A ALV that does not induce lung angiosarcomas, but induces mainly long-la...

Section: Methodsmentioning

confidence: 99%

Rapid induction of B-cell lymphomas: insertional activation of c-myb by avian leukosis virus

Kanter

Smith

Hayward

1988

Self Cite

“…Skeletal muscle. The subgroup A virus muscle tropism could in part explain the occurrence of a muscle disease induced by recombinant ring-necked pheasant viruses with subgroup A but not subgroup F envelope antigens (21). The finding of high levels of replication in the skeletal muscle of chicks inoculated after hatching (Tables 1 and 2) is intriguing because postembryonic skeletal muscle growth involves cell enlargement rather than cell division (11,24) and host cell DNA replication is thought to be required for integration and expression of viral genes (27,28).…”

Section: V-1 and Prav-0 Can Be Found In Robinson Etamentioning

confidence: 99%

Influence of env and long terminal repeat sequences on the tissue tropism of avian leukosis viruses

Brown

Robinson

1988

Adsorption and penetration of retroviruses into eucaryotic cells is mediated by retroviral envelope glycoproteins interacting with host receptors. Recombinant avian leukosis viruses (ALVs) differing only in envelope determinants that interact with host receptors for subgroup A or E ALVs have been found to have unexpectedly distinctive patterns of tissue-specific replication. Recombinants of both subgroups were highly expressed in bursal lymphocytes as well as in cultured chicken embryo fibroblasts. In contrast, the subgroup A but not subgroup E host range allowed high levels of expression in skeletal muscle, while subgroup E but not subgroup A envelope glycoproteins permitted efficient replication in the thymus. A subgroup B virus (RAV-2), like the subgroup E viruses, demonstrated a distinct bursal and thymic tropism, further supporting the theory that genes encoding receptors for subgroup B and E viruses are allelic. The source of long terminal repeats (LTRs) or adjacent sequences also influenced tissue-specific replication, with the LTRs from endogenous virus RAV-O supporting efficient replication in the bursa and thymus but not in skeletal muscle. These results indicate that ALV env and LTR regions are responsible for unexpectedly distinctive tissue tropisms.

“…By this means, a cell harboring one retrovirus excludes additional viruses of the same host range class. Interactions between viral envelope glycoproteins and host cell receptors can also cause specific pathogenic changes, including mitogenesis and cytotoxicity (7,14,18,21,22,28,30,31,35,37,42,44,45,(47)(48)(49)53). Such pathogenesis has been implicated in important retroviral diseases, including human and feline AIDS (7,22,30,31,42,49), leukemias (14,21,27,28,35,47), lymphomas (37), anemias (45,48), hemangioma (44), and neural degeneration (53).…”

mentioning

confidence: 99%

Plasma membrane receptors for ecotropic murine retroviruses require a limiting accessory factor

Wang

Paul

Burgeson

et al. 1991

A retroviral vector was used to express various amounts of the receptor (ecoR) for ecotropic host range murine retroviruses on naturally barren hamster, mink, and human cells. These cells and murine cells were then incubated for 2 h with dilutions of a helper-free ecotropic retrovirus that encodes human growth hormone, and the number of infected cells was later determined by growth hormone-specific immunofluorescence. For all cells under the conditions of these studies, virus adsorption was the limiting step of infection and the cellular capacities for infection were unsaturated either at cell surfaces or at intracellular sites. Thus, infections occurred at low multiplicities of infection per cell and were directly proportional to virus and cell concentrations, and only a small percentage (ca. 5%) of the infectious virions became adsorbed from the medium during the 2-h incubations. Although increasing the adsorption by raising virus or cell concentrations results in more infections in the cultures, increasing adsorption by raising the number of ecoR above a low threshold had no effect on infections. Thus, cells with a low number of ecoR were infected as efficiently as highly adsorbing cells that contained many times more ecoR. To reconcile these results, we conclude that only a small, set number of cell surface ecoR can be functional for infection and that all excess ecoR can only bind virus into an unsalvageable pool. Therefore, retroviral receptors on single cells are functionally diverse. Our results suggest that activity of ecoR in infection requires a limiting second cellular component. * Corresponding author. 25) and for gibbon ape leukemia virus (39) were isolated. Although these receptors appear to be unrelated, they both may be glycoproteins with multiple membrane-spanning regions (1, 39). The ecotropic receptor (ecoR) occurs on cells of mice and rats but not on cells of other species. Genetic analysis has suggested that ecoR may be essential for the viability of cultured murine fibroblasts (16). In this study, we have developed efficient methods to express ecoR cDNA in nonmurine cells. We used these cells to study the role of ecoR in virus binding and infection. Our results suggest that a cellular component in addition to ecoR is required for infection. MATERIALS AND METHODS Cells and viruses. Swiss mouse NIH 3T3 fibroblasts, mink lung CCL64 fibroblasts, Chinese hamster ovary cells (CHO), and human osteogenic sarcoma cells (Ostk-) were from American Type Culture Collection (Rockville, Md.). Ii-2 ecotropic packaging cells (34) and PA-12 amphotropic packaging cells (38) were from R. C. Mulligan (Massachusetts Institute of Technology, Cambridge) and A. D. Miller (Fred Hutchinson Cancer Center, Seattle, Wash.), respectively. CHO cells were grown in alpha minimum essential medium supplemented with 10% fetal bovine serum. Other cells were maintained in Dulbecco's modified Eagle's medium supplemented with 10% fetal bovine serum. Helper-free ecotropic host range viruses from ti-2 cells that encoded the neomycin...