Journal of virology 2017 01 25() pii 10.1128/JVI.00064-17
Open reading frame virion infectivity factor (Vif) is conserved among most lentiviruses. Vif molecules contribute to viral replication by inactivating host anti-viral factors, the APOBEC3 cytidine deaminases. However, various species of lentiviral Vif proteins have evolved different strategies for overcoming host APOBEC3. Whether different species of lentiviral Vif proteins still preserve certain common features has not been reported. Here, we show for the first time that diverse lentiviral Vif molecules maintain the ability to interact with the HIV-1 Gag precursor (Pr55(Gag)) polyprotein. Surprisingly, BIV Vif, but not HIV-1 Vif, interfered with HIV-1 production and viral infectivity even in the absence of APOBEC3. Further analysis revealed that BIV Vif demonstrated an enhanced interaction with Pr55(Gag) when compared to HIV-1 Vif, and BIV Vif defective for the Pr55(Gag) interaction lost its ability to inhibit HIV-1. The C-terminal region of CA and the p2 region of Pr55(Gag), which are important for virus assembly and maturation, were involved in the interaction. Transduction of CD4(+) T cells with BIV Vif blocked HIV-1 replication. Thus, the conserved Vif-Pr55(Gag) interaction provides a potential target for the future development of anti-viral strategies.
The conserved Vif accessory proteins of primate lentiviruses HIV-1, SIV, and BIV all form ubiquitin ligase complexes to target host antiviral APOBEC3 proteins for degradation, with different cellular requirements and using different molecular mechanisms. Here we demonstrate that BIV Vif can interfere with HIV-1 Gag maturation and suppress HIV-1 replication through interaction with the precursor of the Gag (Pr55(Gag)) of HIV-1 in virus-producing cells. Moreover, the HIV-1 and SIV Vif proteins are conserved in terms of their interactions with HIV-1 Pr55(Gag), although HIV-1 Vif proteins bind Pr55(Gag) less efficiently than do those of BIV Vif. Our research not only sheds new light on this feature of these conserved lentiviral Vif proteins but also provides a formerly unrecognized target for the development of anti-viral strategies. Since increasing the Vif-Pr55(Gag) interaction could potentially suppress virus proliferation, this approach could offer a new strategy for the development of HIV inhibitors.