Human immunodeficiency virus-1 BF intersubtype recombinant viral protein U second alpha helix plays an important role in viral release and BST-2 degradation

Abstract

We previously reported a naturally occurring BF intersubtype recombinant viral protein U (Vpu) variant with an augmented capacity to enhance viral replication. Structural analysis of this variant revealed that its transmembrane domain and a-helix I in the cytoplasmic domain (CTD) corresponded to subtype B, whereas the a-helix II in the CTD corresponded to subtype F1. In this study, we aimed to evaluate the role of the Vpu cytoplasmic a-helix II domain in viral release enhancement and in the down-modulation of BST-2 and CD4 from the cell surface. In addition, as serine residues in Vpu amino acid positions 61 or 64 have been shown to regulate Vpu intracellular half-life, which in turn could influence the magnitude of viral release, we also studied the impact of these residues on the VpuBF functions, since S61 and S64 are infrequently found among BF recombinant Vpu variants. Our results showed that the exchange of Vpu a-helix II between subtypes (BAF) directly correlated with the enhancement of viral release and, to a lesser extent, with changes in the capacity of the resulting chimera to down-modulate BST-2 and CD4. No differences in viral release and BST-2 down-modulation were observed between VpuBF and VpuBF-E61S. On the other hand, VpuBF-A64S showed a slightly reduced capacity to enhance viral production, but was modestly more efficient than VpuBF in down-modulating BST-2. In summary, our observations clearly indicate that a-helix II is actively involved in Vpu viral-releasepromoting activity and that intersubtype recombination between subtypes B and F1 created a protein variant with a higher potential to boost the spread of the recombinant strain that harbours it.

Deciphering How HIV‐1 Intersubtype Recombination Shapes Viral Fitness and Disease Progression

“…In an effort to understand the increasing prevalence of CRFs in particular regions of the world, many researchers initiated the study of the in vitro activity of isolated proteins (Nef, Vpu, Tat) or genomic regions (LTR) derived from CRFs, in comparison to the activity of the proteins/regions derived from the parental subtypes ( Woollard et al, 2014 , De Candia et al, 2013 , Turk et al, 2006 , Turk et al, 2009 ). Others went one step further and analyzed the ex vivo replicative fitness of CRFs ( Rubio et al, 2014 , Njai et al, 2006 ).…”