Interferon inhibits the replication of HIV-1, SIV, and SHIV chimeric viruses by distinct mechanisms

Abstract

Interferon (IFN) treatment of lentivirus-infected cells substantially reduces virus replication in vitro. Although the replication of both HIV-1 and simian immunodeficiency virus (SIV) is inhibited, IFN blocks the replication of these viruses at different stages of the viral life cycle. We previously demonstrated that in HIV-1-infected cells, IFN blocks a late step in viral replication, leading to a decrease in viral protein stability and a deregulation of polyprotein processing. In contrast, in SIV-infected cells, IFN blocks an early step in viral replication, between virus binding and reverse transcription. Thus, the viral gene products targeted by IFN may be different for each of these viruses. To attempt to define which viral proteins are targeted by the IFN response, we examined the effects of IFN on the replication of two SIV/HIV-1 (SHIV) chimeric viruses, SHIV-4(vpu+) and SHIV-4(vpu-) in 174 x CEM cells. These viruses were grown from constructs in which the SIVmac239 env, tat, and rev genes have been replaced with those HIV-1. The use of SHIV-4(vpu+) allowed us to examine whether vpu, which is unique to HIV-1, might contribute to the differential effects of IFN on HIV-1 and SIV replication. Surprisingly, we found that IFN inhibited SHIV replication differently than the replication of either HIV-1 or SIV. IFN treatment of SHIV-infected cells resulted in a decrease in the level of viral RNA expression but had no apparent effect on the integration of proviral DNA. Nuclear runoff transcription assays indicated that the reduction of SHIV RNA expression in IFN-treated cells was not due to alterations in RNA polymerase II-mediated transcription, suggesting that IFN may block SHIV replication by promoting the increased degradation of viral RNA. The presence of absence of the vpu gene did not alter the effects of IFN on SHIV replication, indicating that Vpu is not responsible for the differential effect of IFN on HIV-1 and SIV replication. Thus the response of SHIVs to antiviral agents such as IFN may be unique from either HIV-1 or SIV. This may be an important consideration when using SHIVs to evaluate anti-HIV-1 therapies in animal models of AIDS.