Human Tetherin Exerts Strong Selection Pressure on the HIV-1 Group N Vpu Protein

Hiv-1 groups m and n emerged within the last century following two independent cross-species transmissions of sivcpz from chimpanzees to humans. in contrast to pandemic group m strains,hiv-1 group n viruses are exceedingly rare,with only about a dozen infections identified,all but one in individuals from cameroon. poor adaptation to the human host may be responsible for this limited spread of hiv-1 group n in the human population. here,we analyzed the function of vpu proteins from seven group n strains from cameroon,the place where this zoonosis originally emerged. we found that these n-vpus acquired four amino acid substitutions (e15a,v19a and iv25/26ll) in their transmembrane domain (tmd) that allow efficient interaction with human tetherin. however,despite these adaptive changes,most n-vpus still antagonize human tetherin only poorly and fail to down-modulate cd4,the natural killer (nk) cell ligand ntb-a as well as the lipid-antigen presenting protein cd1d. these functional deficiencies were mapped to amino acid changes in the cytoplasmic domain that disrupt putative adaptor protein binding sites and an otherwise highly conserved ßtrcp-binding dsgxxs motif. as a consequence,n-vpus exhibited aberrant intracellular localization and/or failed to recruit the ubiquitin-ligase complex to induce tetherin degradation. the only exception was the vpu of a group n strain recently discovered in france,but originally acquired in togo,which contained intact cytoplasmic motifs and counteracted tetherin as effectively as the vpus of pandemic hiv-1 m strains. these results indicate that hiv-1 group n vpu is under strong host-specific selection pressure and that the acquisition of effective tetherin antagonism may lead to the emergence of viral variants with increased transmission fitness. © 2012 sauter et al.