A TCR-mimic bispecific antibody reduces HIV-1 provirus and delays viral rebound in HLA-matched humanized mice

作者：Zhe Yuan, Nathan L. Board, Miaoyun Zhao, Guorui Zu, Srona Sengupta, Qingsheng Li, Janet D. Siliciano, Robert F. Siliciano, Luis J. Montaner · 发表于：Proceedings of the National Academy of Sciences · 年份：2026 · DOI：10.1073/pnas.2527880123 · 研究领域：Monoclonal and Polyclonal Antibodies Research、HIV Research and Treatment、Immune Cell Function and Interaction

Abstract Bispecific antibodies that reroute cytotoxic effectors toward infected cells are promising HIV-1 cure agents, yet existing formats bind Env and are limited by antigenic variation and Env down-regulation. We engineered a TCR-mimic single-chain diabody, HI12, that recognizes a conserved Pol-derived peptide presented by HLA-A * 02:01 and evaluated its effect in HLA-matched, HIV-infected humanized mice. When administered during early antiretroviral therapy (ART), HI12 was well tolerated, activated HIV-specific CD8 + T cells and accelerated plasma virus decay. Treatment produced four-to six-fold reductions in intact and total proviral DNA within lymph-node and splenic CD4 + T cells, indicating substantive reservoir clearance. After ART interruption, HI12-treated animals showed a significant delay in viral rebound compared with controls, linking reservoir reduction to improved post-therapy control. These findings provide the first in-vivo evidence that a peptide-HLA-directed bispecific antibody can both shrink the intact HIV reservoir and defer viral recrudescence, supporting further development of TCR-mimic bispecific antibodies for cure strategies. Significance Statement An HIV-1 cure strategy will require novel therapeutics to facilitate immune-mediated elimination of infected cells and reduction of blood and tissue reservoirs. Here, we demonstrate that an TCR-mimic bispecific antibody that recognizes a conserved Pol epitope can promote CD8 + T cell-mediated clearance o...