The role of cellular factors in retrovirus replication (Immune deficiency)

Many steps of retrovirus replication are dependent upon cellular factors. Consequently, differential expression patterns of essential cellular factors within a host may govern the pathogenesis of a retrovirus. This is exemplified in infection of sheep by either Enzootic nasal tumor virus (ENTV), or a closely related virus, jaagsiekte sheep retrovirus (JSRV). The work described here shows that ENTV mediates virus entry using the same receptor as does JSRV Env, the candidate tumor suppressor Hyal2. Furthermore, we show that like JSRV, the envelope (Env) protein of ENTV can transform cultured cells and thus is likely to be responsible for oncogenesis in animals. Although these two viruses use the same cell-surface receptor for cell entry and apparently transform cells by the same mechanism, they induce cancer in different tissues of infected sheep, indicating that oncogenesis is regulated at some other level. The transcriptional regulatory elements in these viruses are quite different, suggesting that tissue-specific oncogenesis may be regulated at the level of viral gene expression.; Organisms that lack cellular factors required for retrovirus replication are not permissive to infection by these viruses. We have identified multiple cell lines from fish (FHM), mosquitoes (Mos-55), moths (Sf9, High-5), flies (S2), and frogs (XPK2) that are not efficiently transduced by MoMLV-based or HIV-1-based vectors pseudotyped with many different viral envelope proteins, including VSV-G, while the same vectors are functional in these cells following transfection. A comparison of MoMLV-based vector transduction in mammalian and nonmammalian cells shows that the nonmammalian cells have blocks either at entry, reverse transcription, or integration. Additionally, zebrafish cell lines ZF4, SJD.1, and ZEM2S display attenuation to entry and/or reverse transcription of VSV-G-pseudotyped MoMLV-based vectors, whereas other transduction processes are unaffected. Furthermore, these cells are resistant to transduction by HIV-1-based vectors. The variation of transduction by these vectors in mammalian and nonmammalian cells are not due to differences in culture conditions or cell division rate, but likely the result of divergence in cellular factors required for retroviral transduction. Thus, these cells provide new opportunities for identifying cellular factors that play a role in retroviral replication.