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

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.