{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,26]],"date-time":"2026-09-26T15:04:10Z","timestamp":1790435050623,"version":"4.1.0"},"reference-count":23,"publisher":"Springer Science and Business Media LLC","issue":"7894","license":[{"start":{"date-parts":[[2021,12,7]],"date-time":"2021-12-07T00:00:00Z","timestamp":1638835200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2021,12,7]],"date-time":"2021-12-07T00:00:00Z","timestamp":1638835200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Nature"],"published-print":{"date-parts":[[2022,1,27]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Because no currently available vaccine can prevent HIV infection, pre-exposure prophylaxis (PrEP) with antiretrovirals (ARVs) is an important tool for combating the HIV pandemic<jats:sup>1,2<\/jats:sup>. Long-acting ARVs promise to build on the success of current PrEP strategies, which must be taken daily, by reducing the frequency of administration<jats:sup>3<\/jats:sup>. GS-CA1 is a small-molecule HIV capsid inhibitor with picomolar antiviral potency against a broad array of HIV strains, including variants resistant to existing ARVs, and has shown long-acting therapeutic potential in a mouse model of HIV infection<jats:sup>4<\/jats:sup>. Here we show that a single subcutaneous administration of GS-CA1 provides long-term protection against repeated rectal simian\u2013human immunodeficiency virus (SHIV) challenges in rhesus macaques. Whereas all control animals became infected after 15 weekly challenges, a single 300\u2009mg\u00a0kg<jats:sup>\u2212<\/jats:sup><jats:sup>1<\/jats:sup> dose of GS-CA1 provided per-exposure infection risk reduction of 97% for 24 weeks. Pharmacokinetic analysis showed a correlation between GS-CA1 plasma concentration and protection from SHIV challenges. GS-CA1 levels greater than twice the rhesus plasma protein-adjusted 95% effective concentration conferred 100% protection in this model. These proof-of-concept data support the development of capsid inhibitors as a novel long-acting PrEP strategy in humans.<\/jats:p>","DOI":"10.1038\/s41586-021-04279-4","type":"journal-article","created":{"date-parts":[[2021,12,7]],"date-time":"2021-12-07T17:02:39Z","timestamp":1638896559000},"page":"612-616","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":29,"title":["Long-acting capsid inhibitor protects macaques from repeat SHIV challenges"],"prefix":"10.1038","volume":"601","author":[{"given":"Samuel J.","family":"Vidal","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elena","family":"Bekerman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Derek","family":"Hansen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bing","family":"Lu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kelly","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Judy","family":"Mwangi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"William","family":"Rowe","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Federico","family":"Campigotto","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jim","family":"Zheng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Darryl","family":"Kato","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7821-5552","authenticated-orcid":false,"given":"Abishek","family":"Chandrashekar","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julia","family":"Barrett","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3475-1016","authenticated-orcid":false,"given":"Shivani","family":"Patel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6958-9464","authenticated-orcid":false,"given":"Huahua","family":"Wan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tochi","family":"Anioke","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7769-7326","authenticated-orcid":false,"given":"Noe B.","family":"Mercado","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joseph P.","family":"Nkolola","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Melissa J.","family":"Ferguson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"William J.","family":"Rinaldi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christian","family":"Callebaut","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wade","family":"Blair","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tomas","family":"Cihlar","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Romas","family":"Geleziunas","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephen R.","family":"Yant","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5127-4659","authenticated-orcid":false,"given":"Dan H.","family":"Barouch","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2021,12,7]]},"reference":[{"key":"4279_CR1","unstructured":"World Health Organization. Consolidated Guidelines on the Use of Antiretroviral Drugs for Treating and Preventing HIV Infection: Recommendations for a Public Health Approach, 2nd ed. (World Health Organization Press, 2016)."},{"key":"4279_CR2","doi-asserted-by":"publisher","first-page":"1973","DOI":"10.1097\/QAD.0000000000001145","volume":"30","author":"VA Fonner","year":"2016","unstructured":"Fonner, V. A. et al. Effectiveness and safety of oral HIV preexposure prophylaxis for all populations. AIDS 30, 1973\u20131983 (2016).","journal-title":"AIDS"},{"key":"4279_CR3","doi-asserted-by":"publisher","first-page":"e788","DOI":"10.1016\/S2352-3018(19)30238-3","volume":"6","author":"LE Coelho","year":"2019","unstructured":"Coelho, L. E., Torres, T. S., Veloso, V. G., Landovitz, R. J. & Grinsztejn, B. Pre-exposure prophylaxis 2.0: new drugs and technologies in the pipeline. Lancet HIV 6, e788\u2013e799 (2019).","journal-title":"Lancet HIV"},{"key":"4279_CR4","doi-asserted-by":"publisher","first-page":"1377","DOI":"10.1038\/s41591-019-0560-x","volume":"25","author":"SR Yant","year":"2019","unstructured":"Yant, S. R. et al. A highly potent long-acting small-molecule HIV-1 capsid inhibitor with efficacy in a humanized mouse model. Nat. Med. 25, 1377\u20131384 (2019).","journal-title":"Nat. Med."},{"key":"4279_CR5","doi-asserted-by":"crossref","unstructured":"GBD 2019 Diseases and Injuries Collaborators. Global burden of 369 diseases and injuries in 204 countries and territories, 1990\u20132019: a systematic analysis for the Global Burden of Disease Study 2019. Lancet 396, 1204\u20131222 (2020).","DOI":"10.1016\/S0140-6736(20)30925-9"},{"key":"4279_CR6","doi-asserted-by":"publisher","first-page":"1168","DOI":"10.1126\/science.1193748","volume":"329","author":"Q Abdool Karim","year":"2010","unstructured":"Abdool Karim, Q. et al. Effectiveness and safety of tenofovir gel, an antiretroviral microbicide, for the prevention of HIV infection in women. Science 329, 1168\u20131174 (2010).","journal-title":"Science"},{"key":"4279_CR7","doi-asserted-by":"publisher","first-page":"2587","DOI":"10.1056\/NEJMoa1011205","volume":"363","author":"RM Grant","year":"2010","unstructured":"Grant, R. M. et al. Preexposure chemoprophylaxis for HIV prevention in men who have sex with men. N. Engl. J. Med. 363, 2587\u20132599 (2010).","journal-title":"N. Engl. J. Med."},{"key":"4279_CR8","doi-asserted-by":"publisher","first-page":"399","DOI":"10.1056\/NEJMoa1108524","volume":"367","author":"JM Baeten","year":"2012","unstructured":"Baeten, J. M. et al. Antiretroviral prophylaxis for HIV prevention in heterosexual men and women. N. Engl. J. Med. 367, 399\u2013410 (2012).","journal-title":"N. Engl. J. 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Emtricitabine-tenofovir concentrations and pre-exposure prophylaxis efficacy in men who have sex with men. Sci. Transl. Med. 4, 151ra125 (2012).","journal-title":"Sci. Transl. Med."},{"key":"4279_CR12","doi-asserted-by":"publisher","first-page":"411","DOI":"10.1056\/NEJMoa1202614","volume":"367","author":"L Van Damme","year":"2012","unstructured":"Van Damme, L. et al. Preexposure prophylaxis for HIV infection among African women. N. Engl. J. Med. 367, 411\u2013422 (2012).","journal-title":"N. Engl. J. Med."},{"key":"4279_CR13","doi-asserted-by":"publisher","first-page":"509","DOI":"10.1056\/NEJMoa1402269","volume":"372","author":"JM Marrazzo","year":"2015","unstructured":"Marrazzo, J. M. et al. Tenofovir-based preexposure prophylaxis for HIV infection among African women. N. Engl. J. Med. 372, 509\u2013518 (2015).","journal-title":"N. Engl. J. 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Characterization of HIV infection in cisgender men and transgender women who have sex with men receiving injectable cabotegravir for HIV prevention: HPTN 083. J. Infect. Dis. https:\/\/doi.org\/10.1093\/infdis\/jiab152 (2021).","DOI":"10.1093\/infdis\/jiab152"},{"key":"4279_CR21","unstructured":"Margot, N. et al. Lenacapavir resistance analysis in a phase 1b clinical proof-of-concept study. Paper presented at 2020 HIV Drug Therapy Glasgow, virtual, 5\u20138 October 2020 (2020)."},{"key":"4279_CR22","doi-asserted-by":"publisher","first-page":"595","DOI":"10.1002\/jms.1921","volume":"46","author":"R Ramanathan","year":"2011","unstructured":"Ramanathan, R. et al. It is time for a paradigm shift in drug discovery bioanalysis: from SRM to HRMS. J. Mass Spectrom. 46, 595\u2013601 (2011).","journal-title":"J. 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The authors otherwise declare no potential conflicts of interest.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}]}}