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AUTOLOGOUS NEUTRALISING ANTIBODIES AND EFFECTIVE CD8 T-CELLS MAINTAIN HIV POST-INTERVENTION CONTROL
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CROI 2026 Feb 22-25 Denver
Katie Fisher, Mauro A. Garcia, Giacomo Schmidt Frattari, Junlin Zhuo, Míriam Rosás-Umbert, Lisa L. Dietz, Emma F. Iversen, Itzayana G. Miller, Michael S. Seaman, Henning Gruell, Florian Klein, R. Brad Jones, Janet M. Siliciano, Robert F. Siliciano, Ole S. Søgaard
Program Abstract
Autologous Neutralising Antibodies and Effective CD8 T Cells Maintain HIV Postintervention Control
Katie Fisher1, Mauro A. Garcia2, Giacomo Schmidt Frattari1, Junlin Zhuo2, M.riam Ros.s-Umbert3, Lisa L. Dietz1, Emma F. Iversen1, Itzayana G. Miller4, Michael S. Seaman5, Henning Gruell6, Florian Klein6, R. Brad Jones4, Janet M. Siliciano2,
Robert F. Siliciano2, Ole S. S.gaard1
1Aarhus University, Aarhus, Denmark, 2The Johns Hopkins University School of Medicine, Baltimore, MD, USA, 3University of Montreal, Montreal, Canada, 4Weill Cornell Medicine, New York, NY, USA, 5Beth Israel Deaconess Medical Center, Boston, MA, USA, 6University Hospital Cologne, Cologne, Germany
Background: Interruption of antiretroviral therapy (ART) typically leads to viral rebound within weeks in people with HIV-1. Post-intervention controllers (PICs) control viremia without ART after a therapeutic intervention. We characterised three PICs with suppressed viral load for >6.5 years (ID107), >7.5 years (ID9254) and 2.5 years (ID142) following HIV-1 broadly neutralising antibody administration.
Methods: The intact/inducible proviral reservoir was quantified using quantitative viral outgrowth assays (qVOA). Autologous neutralising antibody responses were assessed using pseudoviruses representing autologous qVOA env variants or qVOA isolates. HIV-1-specific CD8 T-cell responses were analysed by intracellular cytokine staining and further characterised using activation-induced marker (AIM)-sorted T-cells stimulated with HIV-1 peptide pools, followed by single-cell transcriptome and paired abTCR sequencing. The suppression capacity of HIV-1-specific CD8 T-cells was assessed in vivo using a participant-derived xenograft mouse model. For ID142, escape mutations at viral rebound after 2.5 years of ART-free control were characterised using nearfulllength sequencing of plasma-derived HIV-1 genomes.
Results: All PICs had quantifiable inducible proviral reservoirs during ART-free control. Potent aNAb responses against inducible qVOA variants were detected in all PICs, with no evidence of cross-neutralisation capacity against unrelated variants. T-cell responses before ART interruption were characterised by high frequencies of CD8 T-cells that appeared pre-programmed to respond rapidly to HIV-1 antigen stimulation. These HIV-1-specific CD8 T-cell populations were dominated by clones that were present prior to ART interruption, and persisted during ART-free control. Mice engrafted with memory CD4 and CD8 T-cells from ID107 demonstrated direct suppression of autologous virus rebound in vivo. For ID142, viral rebound was caused by a viral variant that was genetically distinct to the persisting proviral reservoir, carrying mutations suggesting escape from aNAb and T-cell responses. Autologous IgG sourced from before and after viral rebound was unable to neutralise pseudoviruses representing rebound HIV-1 env, suggesting complete escape of the rebounding viral population from the potent aNAb response.
Conclusions: Our results show that potent immune responses, including aNAbs and rapidly responding HIV-1-specific CD8 T-cells, are crucial mediators of longterm ART-free control of HIV-1.
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