Combination immunotherapy induces post-intervention control of HIV

Combination immunotherapy induces post-intervention control of HIV | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Biological Sciences - Article Combination immunotherapy induces post-intervention control of HIV Michael Peluso, Demi Sandel, Amelia Deitchman, Sun Jin Kim, Thomas Dalhuisen, and 35 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6141479/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 01 Dec, 2025 Read the published version in Nature → Version 1 posted You are reading this latest preprint version Abstract The identification of therapeutic strategies to induce sustained antiretroviral therapy (ART)-free control of HIV infection is a major priority. Combination immunotherapy including HIV vaccination, immune stimulation/latency reversal, and passive transfer of broadly neutralizing antibodies (bNAbs) has shown promise in non-human primate models, but few studies have translated such approaches into people. Here, we performed a single-arm, proof-of-concept combination study of these three approaches in ten people with HIV on ART that included (1) therapeutic vaccination with an HIV/Gag conserved element (CE)-targeted DNA+IL-12 prime/MVA boost regimen followed by (2) administration of two bNAbs (10-1074 and VRC07-523LS) and a toll-like receptor 9 (TLR9) agonist (lefitolimod) during ART suppression, followed by (3) repeat bNAb administration at the time of ART interruption. Seven of the ten participants exhibited partial (low viral load set point) or complete (aviremic) post-intervention control after stopping ART, independent of residual bNAb plasma levels. Robust expansion of activated CD8+ T cells early in response to rebounding virus correlated with lower viral load set points. These data suggest that combination immunotherapy approaches might prove effective to induce sustained control of HIV by slowing rebound and improving CD8+ T cell responses, and that these approaches should continue to be optimized. Biological sciences/Immunology/Infectious diseases/HIV infections Biological sciences/Immunology/Adaptive immunity/Cellular immunity/Immunological memory Biological sciences/Immunology/Vaccines/DNA vaccines Biological sciences/Immunology/Translational immunology Full Text Additional Declarations Yes there is potential Competing Interest. MJP serves on a DSMB for American Gene Technologies. SGD reports consulting fees from AbbVie, Eli Lilly, Enanta, GSK, Hookipa, and Immunocore, participated on an advisory board for American Gene Technologies, and owns Tendel stock. MHS is founder and shareholder of Pro Biosciences and Teiko.bio, has been a paid consultant for Five Prime, Ono, January, Earli, Astellas, and Indaptus Therapeutics, and reports research funding from Roche/Genentech, Pfizer, Valitor, and Bristol Myers Squibb. MC served on a Gilead scientific advisory board. MCN has a patent to the bNAbs 10-1074 and 3BNC117 issued (Gilead), is on the SAB of Celldex, and reports personal fees from Gilead and Frontier Biosciences. BKF, GNP, and JIM are inventors on US Government-owned patents related to the CE DNA vaccine. MK has received funding to her institution from Gilead Sciences Inc and Intercept Pharmaceuticals and serves as a scientific consultant for Gilead Sciences Inc, GSK pharmaceuticals, and Resolution Therapeutics. JDR and CJP are employees of Labcorp-Monogram Biosciences and shareholders of Labcorp. DS and EV are employees of and hold stock in Gilead Sciences, Inc. Supplementary Files S1TablenoninterventionAE.pdf Supplementary Table 1 S2Participantleveldata.xlsx Supplementary Table 2 S3TableVLPKall.xlsx Supplementary Table 3 S4TablereservoirICSCTVCyTOFdataall.xlsx Supplementary Table 4 S5TableCorrelationsreservoirTcellssetpoint.xlsx Supplementary Table 5 S6FlowCyTOFPanels.xlsx Supplementary Table 6 S7PKEstimatesTable.docx Supplementary Table 7 amfARextendeddataFIGS16Tables14.pdf Extended Data 20250309amfARextendeddatafiguresALL.pdf Extended Data Cite Share Download PDF Status: Published Journal Publication published 01 Dec, 2025 Read the published version in Nature → Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-6141479","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Biological Sciences - Article","associatedPublications":[],"authors":[{"id":429869160,"identity":"b0c0f2ba-0abe-4fad-b7ec-a6e72b89ea2c","order_by":0,"name":"Michael Peluso","email":"","orcid":"https://orcid.org/0000-0003-0585-6230","institution":"Department of Medicine, University of California, San Francisco, San Francisco, CA, 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Data","description":"","filename":"amfARextendeddataFIGS16Tables14.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6141479/v1/4c379b73b3a0d4d41bd96d24.pdf"},{"id":78823180,"identity":"d49d4471-01bb-4997-b95f-ec5fb5fb3c5b","added_by":"auto","created_at":"2025-03-19 12:03:28","extension":"pdf","order_by":9,"title":"","display":"","copyAsset":false,"role":"supplement","size":18116640,"visible":true,"origin":"","legend":"Extended Data","description":"","filename":"20250309amfARextendeddatafiguresALL.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6141479/v1/f6887320f3b29c00cf7a98b1.pdf"}],"financialInterests":"\u003cb\u003eYes\u003c/b\u003e there is potential Competing Interest.\nMJP serves on a DSMB for American Gene Technologies. SGD reports consulting fees from AbbVie, Eli Lilly, Enanta, GSK, Hookipa, and Immunocore, participated on an advisory board for American Gene Technologies, and owns Tendel stock. MHS is founder and shareholder of Pro Biosciences and Teiko.bio, has been a paid consultant for Five Prime, Ono, January, Earli, Astellas, and Indaptus Therapeutics, and reports research funding from Roche/Genentech, Pfizer, Valitor, and Bristol Myers Squibb. MC served on a Gilead scientific advisory board. MCN has a patent to the bNAbs 10-1074 and 3BNC117 issued (Gilead), is on the SAB of Celldex, and reports personal fees from Gilead and Frontier Biosciences. BKF, GNP, and JIM are inventors on US Government-owned patents related to the CE DNA vaccine. MK has received funding to her institution from Gilead Sciences Inc and Intercept Pharmaceuticals and serves as a scientific consultant for Gilead Sciences Inc, GSK pharmaceuticals, and Resolution Therapeutics. JDR and CJP are employees of Labcorp-Monogram Biosciences and shareholders of Labcorp. DS and EV are employees of and hold stock in Gilead Sciences, Inc.","formattedTitle":"Combination immunotherapy induces post-intervention control of HIV","fulltext":[],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":false,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":true,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":true,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"nature-portfolio","isNatureJournal":true,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"","title":"Nature Portfolio","twitterHandle":"","acdcEnabled":false,"dfaEnabled":false,"editorialSystem":"ejp","reportingPortfolio":"","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"","lastPublishedDoi":"10.21203/rs.3.rs-6141479/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6141479/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"The identification of therapeutic strategies to induce sustained antiretroviral therapy (ART)-free control of HIV infection is a major priority. Combination immunotherapy including HIV vaccination, immune stimulation/latency reversal, and passive transfer of broadly neutralizing antibodies (bNAbs) has shown promise in non-human primate models, but few studies have translated such approaches into people. Here, we performed a single-arm, proof-of-concept combination study of these three approaches in ten people with HIV on ART that included (1) therapeutic vaccination with an HIV/Gag conserved element (CE)-targeted DNA+IL-12 prime/MVA boost regimen followed by (2) administration of two bNAbs (10-1074 and VRC07-523LS) and a toll-like receptor 9 (TLR9) agonist (lefitolimod) during ART suppression, followed by (3) repeat bNAb administration at the time of ART interruption. Seven of the ten participants exhibited partial (low viral load set point) or complete (aviremic) post-intervention control after stopping ART, independent of residual bNAb plasma levels. Robust expansion of activated CD8+ T cells early in response to rebounding virus correlated with lower viral load set points. These data suggest that combination immunotherapy approaches might prove effective to induce sustained control of HIV by slowing rebound and improving CD8+ T cell responses, and that these approaches should continue to be optimized.","manuscriptTitle":"Combination immunotherapy induces post-intervention control of HIV","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-03-19 12:03:23","doi":"10.21203/rs.3.rs-6141479/v1","editorialEvents":[],"status":"published","journal":{"display":false,"email":"[email protected]","identity":"nature","isNatureJournal":true,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"nature","sideBox":"Learn more about [Nature](http://www.nature.com/nature/)","snPcode":"","submissionUrl":"","title":"Nature","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"ejp","reportingPortfolio":"Nature","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"117ebed6-4f3e-417f-9b2d-9cfbcab2e150","owner":[],"postedDate":"March 19th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[{"id":45782196,"name":"Biological sciences/Immunology/Infectious diseases/HIV infections"},{"id":45782197,"name":"Biological sciences/Immunology/Adaptive immunity/Cellular immunity/Immunological memory"},{"id":45782198,"name":"Biological sciences/Immunology/Vaccines/DNA vaccines"},{"id":45782199,"name":"Biological sciences/Immunology/Translational immunology"}],"tags":[],"updatedAt":"2026-01-22T08:11:44+00:00","versionOfRecord":{"articleIdentity":"rs-6141479","link":"https://doi.org/10.1038/s41586-025-09929-5","journal":{"identity":"nature","isVorOnly":false,"title":"Nature"},"publishedOn":"2025-12-01 05:00:00","publishedOnDateReadable":"December 1st, 2025"},"versionCreatedAt":"2025-03-19 12:03:23","video":"","vorDoi":"10.1038/s41586-025-09929-5","vorDoiUrl":"https://doi.org/10.1038/s41586-025-09929-5","workflowStages":[]},"version":"v1","identity":"rs-6141479","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6141479","identity":"rs-6141479","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}