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Among these, only Vpu proteins of pandemic HIV-1 group M strains evolved potent activity against the restriction factor tetherin, which inhibits virus release from infected cells. Thus, effective Vpu-mediated tetherin antagonism may have been a prerequisite for the global spread of HIV-1. To determine whether this particular function enhances primary HIV-1 replication and interferon resistance, we introduced mutations into the<jats:italic>vpu<\/jats:italic>genes of HIV-1 group M and N strains to specifically disrupt their ability to antagonize tetherin, but not other Vpu functions, such as degradation of CD4, down-modulation of CD1d and NTB-A, and suppression of NF-\u03baB activity. Lack of particular human-specific adaptations reduced the ability of HIV-1 group M Vpu proteins to enhance virus production and release from primary CD4<jats:sup>+<\/jats:sup>T cells at high levels of type I interferon (IFN) from about 5-fold to 2-fold. Interestingly, transmitted founder HIV-1 strains exhibited higher virion release capacity than chronic control HIV-1 strains irrespective of Vpu function, and group M viruses produced higher levels of cell-free virions than an N group HIV-1 strain. Thus, efficient virus release from infected cells seems to play an important role in the spread of HIV-1 in the human population and requires a fully functional Vpu protein that counteracts human tetherin.<\/jats:p><jats:p><jats:bold>IMPORTANCE<\/jats:bold>Understanding which human-specific adaptations allowed HIV-1 to cause the AIDS pandemic is of great importance. One feature that distinguishes pandemic HIV-1 group M strains from nonpandemic or rare group O, N, and P viruses is the acquisition of mutations in the accessory Vpu protein that confer potent activity against human tetherin. Adaptation was required because human tetherin has a deletion that renders it resistant to the Nef protein used by the SIV precursor of HIV-1 to antagonize this antiviral factor. It has been suggested that these adaptations in Vpu were critical for the effective spread of HIV-1 M strains, but direct evidence has been lacking. Here, we show that these changes in Vpu significantly enhance virus replication and release in human CD4<jats:sup>+<\/jats:sup>T cells, particularly in the presence of IFN, thus supporting an important role in the spread of pandemic HIV-1.<\/jats:p>","DOI":"10.1128\/mbio.00934-16","type":"journal-article","created":{"date-parts":[[2016,8,17]],"date-time":"2016-08-17T00:48:54Z","timestamp":1471394934000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":62,"title":["Vpu-Mediated Counteraction of Tetherin Is a Major Determinant of HIV-1 Interferon Resistance"],"prefix":"10.1128","volume":"7","author":[{"given":"Dorota","family":"Kmiec","sequence":"first","affiliation":[{"name":"Institute of Molecular Virology, Ulm University Medical Center, Ulm, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shilpa S.","family":"Iyer","sequence":"additional","affiliation":[{"name":"Department of Medicine, 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