Simian–Human immunodeficiency viruses expressing chimeric subtype B/C Vpu proteins demonstrate the importance of the amino terminal and transmembrane domains in the rate of CD4+ T cell loss in macaques

AbstractPreviously, we reported that simian–human immunodeficiency viruses expressing either the lab adapted subtype B (SHIVKU-1bMC33) or subtype C (SHIVSCVpu) Vpu proteins of human immunodeficiency virus type 1 (HIV-1) had different rates of CD4+ T cell loss following inoculation into macaques. In this study, we have generated SHIVs that express either the subtype B or subtype C N-terminal (NTD) and transmembrane (TMD) domains and the opposing cytoplasmic domain (SHIVVpuBC, SHIVVpuCB). In culture systems, SHIVVpuBC replicated faster than SHIVVpuCB while both proteins exhibited similar ability to down-modulate CD4 surface expression. Following inoculation into macaques, SHIVVpuBC resulted in rapid CD4+ T cell loss similar to the parental SHIVKU-1bMC33, while the rate of CD4+ T cell loss in those inoculated with SHIVVpuCB was intermediate of SHIVSCVpu and SHIVKU-1bMC33. These results emphasize the importance of the Vpu NTD/TMD region in the rate of CD4+ T cell loss in the pathogenic X4 SHIV/macaque model