Extracellular Tat captures HIV particles generating a pool of infectious virions resistant to broadly neutralizing anti-Env antibodies

Extracellular Tat captures HIV particles generating a pool of infectious virions resistant to broadly neutralizing anti-Env antibodies | 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 Article Extracellular Tat captures HIV particles generating a pool of infectious virions resistant to broadly neutralizing anti-Env antibodies Barbara Ensoli, Vittorio Francavilla, Antonella Tripiciano, Charlene McDanal, and 20 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-9096520/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted You are reading this latest preprint version Abstract HIV vaccines and antibody-based prevention strategies targeting Env have shown limited efficacy. Here, we identify a Tat-dependent mechanism of HIV transmission and immune evasion mediated by extracellular Tat (eTat), a viral protein expressed early after infection and abundantly released into tissues. Extracellular Tat binds heparan sulfate proteoglycans and, when immobilized, mimics extracellular matrix proteins. We show here that immobilized eTat efficiently captures HIV virions from multiple clades and tiers. Although only a small fraction of virions is retained, Tat-bound virus displays enhanced infectivity, particularly at low virus inputs, a process we term Tat-assisted infection. Notably, both first- and second-generation anti-Env broadly neutralizing antibodies (bnAbs) fail to prevent virion capture and show strongly reduced neutralization potency against Tat-captured viruses, irrespective of epitope specificity. In contrast, polyclonal and monoclonal anti-Tat antibodies efficiently block both virus capture and infection. These findings reveal that eTat establishes an extracellular pool of highly infectious, neutralization-resistant virions, providing a mechanistic explanation for the limited efficacy of current Env-focused interventions. Our work identifies Tat as a critical and targetable determinant of HIV infectivity and immune evasion, supporting the inclusion of Tat in next-generation preventive and therapeutic vaccine strategies and in passive immunization approaches combined with bnAbs. Biological sciences/Immunology/Infectious diseases/HIV infections Biological sciences/Immunology Full Text Additional Declarations There is NO Competing Interest. Cite Share Download PDF Status: Under Review 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. 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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-9096520","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":608228689,"identity":"7cd8f6bf-a960-4e32-b19a-7843e27c3c33","order_by":0,"name":"Barbara 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Here, we identify a Tat-dependent mechanism of HIV transmission and immune evasion mediated by extracellular Tat (eTat), a viral protein expressed early after infection and abundantly released into tissues. Extracellular Tat binds heparan sulfate proteoglycans and, when immobilized, mimics extracellular matrix proteins.\r\nWe show here that immobilized eTat efficiently captures HIV virions from multiple clades and tiers. Although only a small fraction of virions is retained, Tat-bound virus displays enhanced infectivity, particularly at low virus inputs, a process we term Tat-assisted infection. Notably, both first- and second-generation anti-Env broadly neutralizing antibodies (bnAbs) fail to prevent virion capture and show strongly reduced neutralization potency against Tat-captured viruses, irrespective of epitope specificity. In contrast, polyclonal and monoclonal anti-Tat antibodies efficiently block both virus capture and infection. These findings reveal that eTat establishes an extracellular pool of highly infectious, neutralization-resistant virions, providing a mechanistic explanation for the limited efficacy of current Env-focused interventions. 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