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Here, we show that HIV-1 CA can bind multiple Nups, and that both natural and manipulated variation in Nup levels impacts HIV-1 infection in a manner that is strikingly dependent on cell-type, cell-cycle, and cyclophilin A (CypA). We also show that Nups mediate the function of the antiviral protein MX2, and that MX2 can variably inhibit non-viral NLS function. Remarkably, both enhancing and inhibiting effects of cyclophilin A and MX2 on various HIV-1 CA mutants could be induced or abolished by manipulating levels of the Nup93 subcomplex, the Nup62 subcomplex, NUP88, NUP214, RANBP2, or NUP153. Our findings suggest that several Nup-dependent \u2018pathways\u2019 are variably exploited by HIV-1 to target host DNA in a cell-type, cell-cycle, CypA and CA-sequence dependent manner, and are differentially inhibited by MX2.<\/jats:p>","DOI":"10.7554\/elife.35738","type":"journal-article","created":{"date-parts":[[2018,8,7]],"date-time":"2018-08-07T08:00:26Z","timestamp":1533628826000},"source":"Crossref","is-referenced-by-count":135,"title":["Nuclear pore heterogeneity influences HIV-1 infection and the antiviral activity of MX2"],"prefix":"10.7554","volume":"7","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4580-1210","authenticated-orcid":true,"given":"Melissa","family":"Kane","sequence":"first","affiliation":[{"name":"Laboratory of Retrovirology, The Rockefeller University, New York, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephanie V","family":"Rebensburg","sequence":"additional","affiliation":[{"name":"Division of Infectious Diseases, University of Colorado School of Medicine, Aurora, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthew A","family":"Takata","sequence":"additional","affiliation":[{"name":"Laboratory of Retrovirology, The Rockefeller University, New York, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Trinity M","family":"Zang","sequence":"additional","affiliation":[{"name":"Laboratory of Retrovirology, The Rockefeller University, New York, United States"},{"name":"Howard Hughes Medical Institute, New York, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masahiro","family":"Yamashita","sequence":"additional","affiliation":[{"name":"Aaron Diamond AIDS Research Center, New York, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mamuka","family":"Kvaratskhelia","sequence":"additional","affiliation":[{"name":"Division of Infectious Diseases, University of Colorado School of Medicine, Aurora, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2368-3719","authenticated-orcid":true,"given":"Paul D","family":"Bieniasz","sequence":"additional","affiliation":[{"name":"Laboratory of Retrovirology, The Rockefeller University, New York, United States"},{"name":"Howard Hughes Medical Institute, New York, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"4374","published-online":{"date-parts":[[2018,8,7]]},"reference":[{"key":"bib1","doi-asserted-by":"publisher","first-page":"4708","DOI":"10.1128\/JVI.05887-11","article-title":"Human immunodeficiency virus type 1 capsid mutation N74D alters cyclophilin A dependence and impairs macrophage infection","volume":"86","author":"Ambrose","year":"2012","journal-title":"Journal of Virology"},{"key":"bib2","doi-asserted-by":"publisher","first-page":"e00745","DOI":"10.7554\/eLife.00745","article-title":"Scaffold nucleoporins Nup188 and 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