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Initially, it was thought that FPs cannot be targeted for therapy because they are hardly accessible. However, an optimized derivative (VIR-576) of an endogenous fragment of \u03b11-antitrypsin, named VIRIP, targeting the gp41 FP reduced viral loads in HIV-1-infected individuals. Characterization of HIV-1 variants selected during long-term cell-culture passage in the presence of a VIRIP derivative suggested that just three mutations in the HIV-1 Env protein might be sufficient for VIRIP resistance and that four subsequent changes restored viral fitness. Here, we show that all seven mutations contribute to reduced viral susceptibility to VIRIP-based inhibitors and demonstrate that the additional changes strongly impair rather than rescue HIV-1 infectivity, fusogenicity, and replication fitness. High genetic barrier to resistance and severe fitness cost support further clinical development of this class of antiviral agents.<\/jats:p>","DOI":"10.1128\/jvi.00733-18","type":"journal-article","created":{"date-parts":[[2018,6,20]],"date-time":"2018-06-20T12:03:19Z","timestamp":1529496199000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":12,"title":["Reduced Susceptibility to VIRIP-Based HIV-1 Entry Inhibitors Has a High Genetic Barrier and Severe Fitness Costs"],"prefix":"10.1128","volume":"92","author":[{"given":"Janis A.","family":"M\u00fcller","sequence":"first","affiliation":[{"name":"Institute of Molecular Virology, Ulm University Medical Center, Ulm, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anna","family":"Gl\u00f6ckle","sequence":"additional","affiliation":[{"name":"Institute of Molecular Virology, Ulm University Medical Center, Ulm, 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