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

PLoS Pathogens

Markus Moll¹  Edward Barker²  Oliver T. Fackler³  Joëlle V. Fritz³  Beatrice H. Hahn⁴  Gerald H. Learn⁴  Frederic Bibollet-Ruche⁴  Frank Kirchhoff⁵  Anke Heigele⁶  Elisabeth Hermkes⁶  Daniel Sauter⁶  Shariq M. Usmani⁶  Silvia F. Kluge⁶  Daniel Unterweger⁶  Michael Vogl⁶  Martine Peeters⁷ 

[1] Center for Infectious Medicine, Department of Medicine, Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm, Sweden;Department of Immunology and Microbiology, Rush University Medical Center, Chicago, Illinois, United States of America;Department of Infectious Diseases, Virology, University Hospital Heidelberg, Heidelberg, Germany;Department of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America;Department of Microbiology, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America;Institute of Molecular Virology, Ulm University Medical Center, Ulm, Germany;Laboratoire Retrovirus UMR145, IRD and Université Montpellier, BP64501, Montpellier, France

关键词: HIV-1;    293T cells;    Sequence motif analysis;    Sequence alignment;    Cell staining;    Sequence databases;    Beetles;    Multiple alignment calculation;   

DOI  :  10.1371/journal.ppat.1003093

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

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.

【 授权许可】

CC BY