Retrovirus Biology

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We have performed detailed structure-function studies of the HIV-1 Rev Response Element and of an analogous element in the RNA of the HERV-K human endogenous virus. The results of these studies have important implications for the origin of specificity in the interactions of these RNA elements with virus-coded regulatory proteins. These interactions are critical for virus replication, as they make it possible for the export of both spliced and unspliced viral RNAs from the nucleus. It has recently been found that the cellular protein Serinc5 somehow interferes with the ability of HIV-1 particles assembled in Serinc5-containing cells to successfully enter new host cells. The HIV-1 Nef protein counteracts the effects of Serinc5. We have found that Serinc5 also blocks the entry of many other retroviruses; both murine leukemia viruses (MLVs, which are members of the gammaretrovirus genus) and equine infectious anemia virus (like HIV-1, a lentivirus) encode "accessory proteins" that counter the effects of Serinc5. The mechanism of Serinc5 action is not understood. We have systematically surveyed retroviruses for their sensitivity to Serinc5; the purpose of these studies is to try to identify a common feature that might be the target for Serinc5 action. We found that retroviruses differ widely with respect to Serinc5 sensitivity, but we have not yet discerned a pattern underlying these differences. We have also collaborated with Dr. Alex Compton (HIV DRP) in a study of the effects of another antiviral protein, i.e., interferon-induced transmembrane protein 3 (IFITM3). Interestingly, the same MLV accessory protein counteracts the effects of both Serinc5 and IFITM3. We are also analyzing the antiviral action of mouse Apobec3 (mA3), which has strikingly different effects on HIV-1 and MLVs. In collaboration with Dr. John Briggs and others, we found that the structures of mature HIV-1 and MLV particles are remarkably different; it seems possible that these structural differences are responsible for the differences in their response to mA3. We are exploring this possibility in several ways, including testing the effects of chimeras between mA3 and the well-characterized human APOBEC3G. ______We are also studying the properties of MuERV-L, a family of retrotransposons expressed in very early mouse embryogenesis. The functional significance of this expression is unknown.