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Type II IFN (IFN-\u03b3) also induces an antiviral state but is often primarily considered to be an immunomodulatory cytokine. We report that IFN-\u03b3 stimulation can induce an antiviral state that can be both distinct from that of type I interferon and can potently inhibit HIV-1 in primary CD4<jats:sup>+<\/jats:sup>T cells and a number of human cell lines. Strikingly, we find that transmitted\/founder (TF) HIV-1 viruses can resist a late block that is induced by type II IFN, and the use of chimeric IFN-\u03b3-sensitive\/resistant viruses indicates that interferon resistance maps to the<jats:italic>env<\/jats:italic>gene. Simultaneously,<jats:italic>in vitro<\/jats:italic>evolution also revealed that just a single amino acid substitution in the envelope can confer substantial resistance to IFN-mediated inhibition. Thus, the<jats:italic>env<\/jats:italic>gene of transmitted HIV-1 confers resistance to a late block that is phenotypically distinct from blocks previously described to be resisted by<jats:italic>env<\/jats:italic>and is therefore mediated by unknown IFN-\u03b3-stimulated factor(s) in human CD4<jats:sup>+<\/jats:sup>T cells and cell lines. This important unidentified block could play a key role in constraining HIV-1 transmission.<\/jats:p><jats:p><jats:bold>IMPORTANCE<\/jats:bold>The human immune system can hinder invading pathogens through interferon (IFN) signaling. One consequence of this signaling is that cells enter an antiviral state, increasing the levels of hundreds of defenses that can inhibit the replication and spread of viruses. The majority of HIV-1 infections result from a single virus particle (the transmitted\/founder) that makes it past these defenses and colonizes the host. Thus, the founder virus is hypothesized to be a relatively interferon-resistant entity. Here, we show that certain HIV-1 envelope genes have the unanticipated ability to resist specific human defenses mediated by different types of interferons. Strikingly, the envelope gene from a founder HIV-1 virus is far better at evading these defenses than the corresponding gene from a common HIV-1 lab strain. Thus, these defenses could play a role in constraining the transmission of HIV-1 and may select for transmitted viruses that are resistant to this IFN-mediated inhibition.<\/jats:p>","DOI":"10.1128\/jvi.02254-16","type":"journal-article","created":{"date-parts":[[2017,1,19]],"date-time":"2017-01-19T02:10:54Z","timestamp":1484791854000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":23,"title":["The Envelope Gene of Transmitted HIV-1 Resists a Late Interferon Gamma-Induced Block"],"prefix":"10.1128","volume":"91","author":[{"given":"Suzannah J.","family":"Rihn","sequence":"first","affiliation":[{"name":"MRC\u2014University of Glasgow Centre for Virus Research, Institute of Infection, Inflammation and Immunity, University of Glasgow, Glasgow, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Toshana L.","family":"Foster","sequence":"additional","affiliation":[{"name":"Department of Infectious Diseases, King's College London Faculty of Life Sciences and Medicine, Guy's Hospital, London, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Idoia","family":"Busnadiego","sequence":"additional","affiliation":[{"name":"MRC\u2014University of Glasgow Centre for Virus Research, Institute of Infection, Inflammation and Immunity, University of Glasgow, Glasgow, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Muhamad Afiq","family":"Aziz","sequence":"additional","affiliation":[{"name":"MRC\u2014University of Glasgow Centre for Virus Research, Institute of Infection, Inflammation and Immunity, University of Glasgow, Glasgow, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joseph","family":"Hughes","sequence":"additional","affiliation":[{"name":"MRC\u2014University of Glasgow Centre for Virus Research, Institute of Infection, Inflammation and Immunity, University of Glasgow, Glasgow, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stuart J. 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