{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,21]],"date-time":"2026-10-21T07:52:27Z","timestamp":1792569147944,"version":"4.5.0"},"reference-count":50,"publisher":"National Academy of Sciences","issue":"14","license":[{"start":{"date-parts":[[2025,4,1]],"date-time":"2025-04-01T00:00:00Z","timestamp":1743465600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/100030692","name":"HHS | NIH | NIDA | Intramural Research Program","doi-asserted-by":"publisher","award":["Z1A BC011436"],"award-info":[{"award-number":["Z1A BC011436"]}],"id":[{"id":"10.13039\/100030692","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2025,4,8]]},"abstract":"<jats:p>Lenacapavir (GS-6207; LEN) is a potent HIV-1 capsid inhibitor approved for treating multidrug-resistant infection. LEN binds to a hydrophobic pocket between neighboring capsid (CA) proteins in hexamers and stabilizes the capsid lattice, but its effect on HIV-1 capsids is not fully understood. Here, we labeled HIV-1 capsids with green fluorescent protein fused to CA (GFP-CA) or a fluid-phase GFP content marker (cmGFP) to assess LEN\u2019s impact on HIV-1 capsids. HIV-1 cores labeled with GFP-CA, but not cmGFP, could be immunostained with an anti-GFP antibody and were less sensitive to the capsid-binding host restriction factor MX2, demonstrating that GFP-CA is incorporated into the capsid lattice and is a marker for capsid lattice stability, whereas cmGFP is an indicator of core integrity. LEN treatment of isolated HIV-1 cores resulted in a dose-dependent loss of cmGFP signal while preserving the GFP-CA signal, indicating that LEN disrupts core integrity but stabilizes the capsid lattice. In contrast, capsid inhibitor PF-3450074 (PF74) induced loss of core integrity and the capsid lattice. Electron microscopy of LEN- or PF74-treated viral cores revealed frequent breakage at the narrow end of the capsid and other morphological changes. Our results suggest that LEN treatment does not prevent nuclear envelope docking but inhibits nuclear import of cores with or without loss of core integrity. In contrast, PF74 treatment blocks nuclear import by inhibiting the nuclear envelope docking of viral cores, highlighting their different mechanisms of nuclear import inhibition.<\/jats:p>","DOI":"10.1073\/pnas.2420497122","type":"journal-article","created":{"date-parts":[[2025,4,1]],"date-time":"2025-04-01T12:14:43Z","timestamp":1743509683000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":36,"title":["Lenacapavir disrupts HIV-1 core integrity while stabilizing the capsid lattice"],"prefix":"10.1073","volume":"122","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2789-967X","authenticated-orcid":false,"given":"Chenglei","family":"Li","sequence":"first","affiliation":[{"name":"Viral Mutation Section, HIV Dynamics and Replication Program, Center for Cancer Research, National Cancer Institute at Frederick","place":["Frederick"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ryan C.","family":"Burdick","sequence":"additional","affiliation":[{"name":"Viral Mutation Section, HIV Dynamics and Replication Program, Center for Cancer Research, National Cancer Institute at Frederick","place":["Frederick"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rokeya","family":"Siddiqui","sequence":"additional","affiliation":[{"name":"Viral Mutation Section, HIV Dynamics and Replication Program, Center for Cancer Research, National Cancer Institute at Frederick","place":["Frederick"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2341-1526","authenticated-orcid":false,"given":"Sanath Kumar","family":"Janaka","sequence":"additional","affiliation":[{"name":"Viral Mutation Section, HIV Dynamics and Replication Program, Center for Cancer Research, National Cancer Institute at Frederick","place":["Frederick"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ru-ching","family":"Hsia","sequence":"additional","affiliation":[{"name":"Electron Microscopy Laboratory, Cancer Research Technology Program, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research","place":["Frederick"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7733-623X","authenticated-orcid":false,"given":"Wei-Shau","family":"Hu","sequence":"additional","affiliation":[{"name":"Viral Recombination Section, HIV Dynamics and Replication Program, Center for Cancer Research, National Cancer Institute at Frederick","place":["Frederick"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2441-8412","authenticated-orcid":false,"given":"Vinay K.","family":"Pathak","sequence":"additional","affiliation":[{"name":"Viral Mutation Section, HIV Dynamics and Replication Program, Center for Cancer Research, National Cancer Institute at Frederick","place":["Frederick"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2025,4]]},"reference":[{"key":"e_1_3_4_1_2","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-virology-020922-110929"},{"key":"e_1_3_4_2_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.aah4972"},{"key":"e_1_3_4_3_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2009.04.063"},{"key":"e_1_3_4_4_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1920631117"},{"key":"e_1_3_4_5_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2019467118"},{"key":"e_1_3_4_6_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1706245114"},{"key":"e_1_3_4_7_2","doi-asserted-by":"crossref","DOI":"10.7554\/eLife.34772","article-title":"Kinetics of HIV-1 capsid uncoating revealed by single-molecule analysis","volume":"7","author":"Marquez C. 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Schifferdecker , Direct capsid labeling of infectious HIV-1 by genetic code expansion allows detection of largely complete nuclear capsids and suggests nuclear entry of HIV-1 complexes via common routes. mBio 13, e0195922 (2022).","journal-title":"mBio"},{"key":"e_1_3_4_14_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2021.01.025"},{"key":"e_1_3_4_15_2","doi-asserted-by":"crossref","first-page":"377","DOI":"10.1093\/infdis\/jiaa683","article-title":"Clinical impact of pretreatment human immunodeficiency virus drug resistance in people initiating nonnucleoside reverse transcriptase inhibitor-containing antiretroviral therapy: A systematic review and meta-analysis","volume":"224","author":"Bertagnolio S.","year":"2021","unstructured":"S. Bertagnolio , Clinical impact of pretreatment human immunodeficiency virus drug resistance in people initiating nonnucleoside reverse transcriptase inhibitor-containing antiretroviral therapy: A systematic review and meta-analysis. J. 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