Nef Proteins of Epidemic HIV-1 Group O Strains Antagonize Human Tetherin

• Published in: Cell host & microbe Vol. 16; no. 5; pp. 639 - 650
• Main Authors: Kluge, Silvia F., Mack, Katharina, Iyer, Shilpa S., Pujol, François M., Heigele, Anke, Learn, Gerald H., Usmani, Shariq M., Sauter, Daniel, Joas, Simone, Hotter, Dominik, Bibollet-Ruche, Frederic, Plenderleith, Lindsey J., Peeters, Martine, Geyer, Matthias, Sharp, Paul M., Fackler, Oliver T., Hahn, Beatrice H., Kirchhoff, Frank
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 12.11.2014
• Subjects: Amino Acid Sequence; Antigens, CD - genetics; Antigens, CD - metabolism; CD4-Positive T-Lymphocytes - virology; Cell Line, Tumor; Endocytosis; Evolution, Molecular; GPI-Linked Proteins - antagonists & inhibitors; GPI-Linked Proteins - genetics; GPI-Linked Proteins - metabolism; HEK293 Cells; HIV-1 - classification; HIV-1 - pathogenicity; Humans; Molecular Sequence Data; nef Gene Products, Human Immunodeficiency Virus - genetics; nef Gene Products, Human Immunodeficiency Virus - metabolism; Protein Conformation; Sequence Analysis; Sequence Deletion; Virion - genetics; Virion - metabolism
• ISSN: 1931-3128; 1934-6069; 1934-6069
• DOI: 10.1016/j.chom.2014.10.002

Most simian immunodeficiency viruses use their Nef protein to antagonize the host restriction factor tetherin. A deletion in human tetherin confers Nef resistance, representing a hurdle to successful zoonotic transmission. HIV-1 group M evolved to utilize the viral protein U (Vpu) to counteract tetherin. Although HIV-1 group O has spread epidemically in humans, it has not evolved a Vpu-based tetherin antagonism. Here we show that HIV-1 group O Nef targets a region adjacent to this deletion to inhibit transport of human tetherin to the cell surface, enhances virion release, and increases viral resistance to inhibition by interferon-α. The Nef protein of the inferred common ancestor of group O viruses is also active against human tetherin. Thus, Nef-mediated antagonism of human tetherin evolved prior to the spread of HIV-1 group O and likely facilitated secondary virus transmission. Our results may explain the epidemic spread of HIV-1 group O. [Display omitted] •HIV-1 group O Nef targets a distinct region adjacent to the deletion in human tetherin•Nef from the most recent common ancestor of HIV-1 group O counteracts human tetherin•HIV-1 O Nef proteins suppress anterograde transport of tetherin to the cell surface•Nef-mediated human tetherin downmodulation reduces IFNα sensitivity of HIV-1 group O HIV-1 group O has infected about 100,000 individuals, but its mechanism of tetherin antagonism remained unknown. Kluge et al. find that group O Nef proteins evolved to counteract human tetherin by targeting a domain adjacent to a deletion that confers resistance against primate lentiviral Nef proteins, explaining the spread of HIV-1 group O.