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

• 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

SummaryMost 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.

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