title: Human tetherin exerts strong selection pressure on the HIV-1 group N Vpu protein.
abstract: 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.
authors: Institute of Molecular Virology, Ulm University Medical Center, Ulm, Germany.
authors: Daniel
authors: D
authors: Sauter
authors: Daniel
authors: D
authors: Unterweger
authors: Michael
authors: M
authors: Vogl
authors: Shariq M
authors: SM
authors: Usmani
authors: Anke
authors: A
authors: Heigele
authors: Silvia F
authors: SF
authors: Kluge
authors: Elisabeth
authors: E
authors: Hermkes
authors: Markus
authors: M
authors: Moll
authors: Edward
authors: E
authors: Barker
authors: Martine
authors: M
authors: Peeters
authors: Gerald H
authors: GH
authors: Learn
authors: Frederic
authors: F
authors: Bibollet-Ruche
authors: Joëlle V
authors: JV
authors: Fritz
authors: Oliver T
authors: OT
authors: Fackler
authors: Beatrice H
authors: BH
authors: Hahn
authors: Frank
authors: F
authors: Kirchhoff
mesh_terms: D000595:Amino Acid Sequence; D015703:Antigens, CD / Q000378:metabolism*; D001665:Binding Sites; D015153:Blotting, Western; D002478:Cells, Cultured; D005434:Flow Cytometry; D058851:GPI-Linked Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D015658:HIV Infections / Q000378:metabolism / Q000821:virology*; D015497:HIV-1 / Q000378:metabolism* / Q000472:pathogenicity; D054298:Human Immunodeficiency Virus Proteins / Q000378:metabolism*; D006801:Humans; D008969:Molecular Sequence Data; D054730:Protein Interaction Domains and Motifs; D012641:Selection, Genetic; D017386:Sequence Homology, Amino Acid; D054334:Viral Regulatory and Accessory Proteins / Q000378:metabolism*; D057074:Virus Release; D000074010:Bone Marrow Stromal Antigen 2; D000086082:Viroporin Proteins
chemical_list: D015703:Antigens, CD; D058851:GPI-Linked Proteins; D054298:Human Immunodeficiency Virus Proteins; D054334:Viral Regulatory and Accessory Proteins; C094572:BST2 protein, human; D000074010:Bone Marrow Stromal Antigen 2; C514859:vpu protein, Human immunodeficiency virus 1; D000086082:Viroporin Proteins