Journal Article

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

Fritz, Joëlle V., Bibollet-Ruche, Frederic, Usmani, Shariq M., Peeters, Martine, Heigele, Anke, Hahn, Beatrice H., Sauter, Daniel, Unterweger, Daniel, Hermkes, Elisabeth, Kirchhoff, Frank, Vogl, Michael, Learn, Gerald H., Kluge, Silvia F., Fackler, Oliver T., Moll, Markus, Barker, Edward

2012

Overview

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.

• Publisher: Public Library of Science,Public Library of Science (PLoS)
• Subject: Acquired immune deficiency syndrome / Acquisitions & mergers / AIDS / Amino Acid Sequence / Amino acids / Antigens, CD - metabolism / Binding Sites / Blotting, Western / Cells, Cultured / Experiments / Flow Cytometry / GPI-Linked Proteins - antagonists & inhibitors / GPI-Linked Proteins - metabolism / Health aspects / HIV / HIV (Viruses) / HIV Infections - metabolism / HIV Infections - virology / HIV-1 - metabolism / HIV-1 - pathogenicity / Host-parasite relationships / Human immunodeficiency virus / Human Immunodeficiency Virus Proteins - metabolism / Human populations / Humans / Killer cells / Ligands / Medicine / Molecular Sequence Data / Pandemics / Physiological aspects / Protein Interaction Domains and Motifs / Proteins / Selection, Genetic / Sequence Homology, Amino Acid / Viral proteins / Viral Regulatory and Accessory Proteins - metabolism / Virulence (Microbiology) / Virus Release / Viruses