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

Previously, we reported that simian-human immunodeficiency viruses expressing either the lab adapted subtype B (SHIV_KU-1bMC33) or subtype C (SHIV_SCVpu) 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 (SHIV_VpuBC, SHIV_VpuCB). In culture systems, SHIV_VpuBC replicated faster than SHIV_VpuCB while both proteins exhibited similar ability to down-modulate CD4 surface expression. Following inoculation into macaques, SHIV_VpuBC resulted in rapid CD4⁺ T cell loss similar to the parental SHIV_KU-1bMC33, while the rate of CD4⁺ T cell loss in those inoculated with SHIV_VpuCB was intermediate of SHIV_SCVpu and SHIV_KU-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.