Abstract
BackgroundHIV-1 viruses are categorized into four distinct groups: M, N, O and P. Despite the same genomic organization, only the group M viruses are responsible for the world-wide pandemic of AIDS, suggesting better adaptation to human hosts. Previously, it has been reported that the group M Vpu protein is capable of both down-modulating CD4 and counteracting BST-2/tetherin restriction, while the group O Vpu cannot antagonize tetherin. This led us to investigate if group O, and the related group P viruses, possess functional anti-tetherin activities in Vpu or another viral protein, and to further map the residues required for group M Vpu to counteract human tetherin.ResultsWe found a lack of activity against human tetherin for both the Vpu and Nef proteins from group O and P viruses. Furthermore, we found no evidence of anti-human tetherin activity in a fully infectious group O proviral clone, ruling out the possibility of an alternative anti-tetherin factor in this virus. Interestingly, an activity against primate tetherins was retained in the Nef proteins from both a group O and a group P virus. By making chimeras between a functional group M and non-functional group O Vpu protein, we were able to map the first 18 amino acids of group M Vpu as playing an essential role in the ability of the protein to antagonize human tetherin. We further demonstrated the importance of residue alanine-18 for the group M Vpu activity. This residue lies on a diagonal face of conserved alanines in the TM domain of the protein, and is necessary for specific Vpu-tetherin interactions.ConclusionsThe absence of human specific anti-tetherin activities in HIV-1 group O and P suggests a failure of these viruses to adapt to human hosts, which may have limited their spread.
Highlights
HIV-1 viruses are categorized into four distinct groups: M, N, O and P
All four groups of HIV-1 originated from the SIVcpz that infects Pan troglodytes troglodytes (Ptt) chimpanzees [18], they are interspersed among the present day SIVcpz Ptt lineages in distinct clusters, suggesting that each group arose by an independent ape to human transmission event [19,20]
HIV-1 group O and P Vpu proteins do not counteract human tetherin To evaluate anti-tetherin activity in the non-pandemic HIV-1 groups, we examined the ability of Vpu proteins from groups O and P to counteract human tetherin restriction (Figure 1)
Summary
HIV-1 viruses are categorized into four distinct groups: M, N, O and P. It has been reported that the group M Vpu protein is capable of both down-modulating CD4 and counteracting BST-2/tetherin restriction, while the group O Vpu cannot antagonize tetherin This led us to investigate if group O, and the related group P viruses, possess functional anti-tetherin activities in Vpu or another viral protein, and to further map the residues required for group M Vpu to counteract human tetherin. This restriction is counteracted by antitetherin activities present in either the Vpu, Nef or Env proteins [1,2,3,4,5,6,7,8,9,10,11] Several of these interactions are speciesspecific, suggesting that selection to evolve and maintain anti-tetherin functions has been part of the adaptation of the viruses to their hosts. HIV-1 groups M and N, and SIVcpz, are phylogenetically approximately equidistant from each other, while HIV-1 groups O and P are more closely related to the recently discovered SIVgor [17,18,21,22]
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