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

Abstract

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.

Involvement of a C-terminal motif in the interference of primate lentiviral Vpu proteins with CD1d-mediated antigen presentation

“…There is accumulating evidence that HIV-1 subtype B and C Vpu proteins differ in their functional properties. Whereas B Vpus degrade CD4 efficiently and interfere with tetherin expression and virus particle release, some studies have shown that C Vpus are less potent in these functions although the number of Vpu proteins analyzed was limited 32 40 41 . In this study, comparing 12 subtype B and 9 subtype C Vpu proteins, we found that subtype C Vpus were significantly weaker CD1d antagonists than their subtype B counterparts ( Fig.…”

A comparative mutational analysis of HIV-1 Vpu subtypes B and C for the identification of determinants required to counteract BST-2/Tetherin and enhance viral egress

“…While this manuscript was in preparation a study using SHIVs expressing chimeric Vpu molecules composed of either a Vpu B N -terminus (luminal and transmembrane domains) with a Vpu C C -terminus or its reciprocal concluded that the in vivo rate of CD4+ T-cell loss in macaques was dependent on the source of the Vpu N -terminus. The SHIV expressing the chimeric Vpu with the N -terminus derived from Vpu B had a more rapid loss of T-cells compared to the chimeric Vpu composed of the Vpu C N -terminus or the parental Vpu C (Ruiz et al, 2012). A mechanism for the increased pathogenesis associated with the N -terminus from Vpu B was not readily apparent.…”

The Envelope Cytoplasmic Tail of HIV-1 Subtype C Contributes to Poor Replication Capacity through Low Viral Infectivity and Cell-to-Cell Transmission

“…In our experimental design, recombination between the Env or EnvEC backbone and the Env or EnvEC amplicon occurs within Vpu, although it is not known where the breakpoint occurs. Vpu is a frequent breakpoint for inter-subtype recombination in vivo [ 122 ] and may impact its efficiency in down modulating BST-2 [ 122 , 123 ] and viruses with recombinant BC [ 123 ] and BF [ 122 ] Vpu are moderately more efficient than subtype B or CB recombinant Vpu in down-modulating BST-2. In our study, viral release tended to be higher for viruses with subtype C gp41CT than for their isogenic counterpart with the gp41CT of NL4.3 ( Fig 4 ).…”