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

摘要

Previously, 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, the 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.