Inhibitory potential of autologous neutralizing antibodies sets quantitative limits on the rebound-competent HIV-1 reservoir
5 affiliations
- 1Department of Medicine, Johns Hopkins University School of Medicine
- 2Department of Global Health, University of Washington
- 3Infectious Disease Division, Fred Hutchinson Cancer Center
- 4Department of Medicine, University of California
- 5Howard Hughes Medical Institute
Abstract
HIV-1 cure requires preventing viral rebound after treatment interruption, but quantitative criteria defining the rebound-competent reservoir are lacking. We studied individuals undergoing observational treatment interruption without confounding interventions to identify virologic and immunologic determinants of rebound. In 9 of 13 participants, rebound viruses were genetically identical or similar to proviruses in circulating resting CD4 + T-cells. We found no evidence of recombination among rebound sequences. Instead, resistance to autologous neutralizing antibodies (aNAbs) was a critical determinant of viral rebound. Increased suppression of viral outgrowth by contemporaneous IgG isolated from plasma was correlated with longer time to rebound. Using inhibitory potential ( IP ), the log reduction in single-round infection at physiologic IgG concentrations, we defined quantitative limits governing rebound-competency with respect to contemporaneous aNAbs. Contemporaneous IgG antibodies inhibited different reservoir variants with a wide range of IP values (0.4-8.2 logs), whereas rebound viruses were minimally inhibited (0.5-2.8 logs), indicating that inhibition by even up to 2.8 logs (631-fold) cannot prevent rebound. Longitudinal analyses revealed that waning aNAb potency over time on ART allows previously neutralized variants to gain rebound potential, consistent with the finding that rebound can come from variants deposited in the reservoir at different pre-ART time points. Thus, rebound competency is a dynamic, immune-governed property defined by quantitative immunologic constraints, including those exerted by aNAbs. SIGNIFICANCE STATEMENT Preventing viral rebound after treatment interruption is the goal of HIV-1 cure research, but the latent proviruses responsible remain undefined. Although rebound is initiated in lymphoid tissues, we found rebound viruses are genetically similar to proviruses in circulating resting CD4 + T-cells. Rebound is not explained by recombination and is not solely from proviruses seeded at treatment initiation. Instead, rebound potential is governed by autologous neutralizing antibodies (aNAbs). We define a quantitative threshold of aNAb-mediated inhibition identifying reservoir variants with rebound potential. During treatment, waning aNAb levels allow previously neutralized variants to become rebound-competent. Thus rebound-competency is not a static property, but a dynamic immune-governed feature. Durable aNAb responses against all rebound-competent reservoir variants may be required for functional HIV-1 cure.
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BibTeX
@article{garcia2026inhibitory,
title = {{Inhibitory potential of autologous neutralizing antibodies sets quantitative limits on the rebound-competent HIV-1 reservoir}},
author = {Mauro A. Garcia and Anna Farrell-Sherman and Beril Aydin and Junlin Zhuo and Emily J. Fray and Anna M. Zinsser and Jun Lai and Kirsten J. Sowers and Haoyue Li and Brianna M. Lopez and Anthony Abeyta-Lopez and Tifany Chu and Donald Lubbeck and Moonki Chae and Niklas Bachmann and Joseph Varriale and Dylan H. Westfall and Rebecca Hoh and Thomas Dalhuisen and Francesco Roberto Simonetti and Michael J. Peluso and Steven G. Deeks and Robert F. Siliciano and Lillian B. Cohn and Janet D'Angelo Siliciano},
journal = {Proceedings of the National Academy of Sciences},
year = {2026},
month = jul,
doi = {10.1073/pnas.2608337123},
url = {https://doi.org/10.1073/pnas.2608337123},
note = {CC BY-NC-ND},
}
RIS
TY - JOUR
TI - Inhibitory potential of autologous neutralizing antibodies sets quantitative limits on the rebound-competent HIV-1 reservoir
AU - Mauro A. Garcia
AU - Anna Farrell-Sherman
AU - Beril Aydin
AU - Junlin Zhuo
AU - Emily J. Fray
AU - Anna M. Zinsser
AU - Jun Lai
AU - Kirsten J. Sowers
AU - Haoyue Li
AU - Brianna M. Lopez
AU - Anthony Abeyta-Lopez
AU - Tifany Chu
AU - Donald Lubbeck
AU - Moonki Chae
AU - Niklas Bachmann
AU - Joseph Varriale
AU - Dylan H. Westfall
AU - Rebecca Hoh
AU - Thomas Dalhuisen
AU - Francesco Roberto Simonetti
AU - Michael J. Peluso
AU - Steven G. Deeks
AU - Robert F. Siliciano
AU - Lillian B. Cohn
AU - Janet D'Angelo Siliciano
PY - 2026
DA - 2026/07/02
JO - Proceedings of the National Academy of Sciences
DO - 10.1073/pnas.2608337123
UR - https://doi.org/10.1073/pnas.2608337123
AB - HIV-1 cure requires preventing viral rebound after treatment interruption, but quantitative criteria defining the rebound-competent reservoir are lacking. We studied individuals undergoing observational treatment interruption without confounding interventions to identify virologic and immunologic determinants of rebound. In 9 of 13 participants, rebound viruses were genetically identical or similar to proviruses in circulating resting CD4 + T-cells. We found no evidence of recombination among rebound sequences. Instead, resistance to autologous neutralizing antibodies (aNAbs) was a critical determinant of viral rebound. Increased suppression of viral outgrowth by contemporaneous IgG isolated from plasma was correlated with longer time to rebound. Using inhibitory potential ( IP ), the log reduction in single-round infection at physiologic IgG concentrations, we defined quantitative limits governing rebound-competency with respect to contemporaneous aNAbs. Contemporaneous IgG antibodies inhibited different reservoir variants with a wide range of IP values (0.4-8.2 logs), whereas rebound viruses were minimally inhibited (0.5-2.8 logs), indicating that inhibition by even up to 2.8 logs (631-fold) cannot prevent rebound. Longitudinal analyses revealed that waning aNAb potency over time on ART allows previously neutralized variants to gain rebound potential, consistent with the finding that rebound can come from variants deposited in the reservoir at different pre-ART time points. Thus, rebound competency is a dynamic, immune-governed property defined by quantitative immunologic constraints, including those exerted by aNAbs. SIGNIFICANCE STATEMENT Preventing viral rebound after treatment interruption is the goal of HIV-1 cure research, but the latent proviruses responsible remain undefined. Although rebound is initiated in lymphoid tissues, we found rebound viruses are genetically similar to proviruses in circulating resting CD4 + T-cells. Rebound is not explained by recombination and is not solely from proviruses seeded at treatment initiation. Instead, rebound potential is governed by autologous neutralizing antibodies (aNAbs). We define a quantitative threshold of aNAb-mediated inhibition identifying reservoir variants with rebound potential. During treatment, waning aNAb levels allow previously neutralized variants to become rebound-competent. Thus rebound-competency is not a static property, but a dynamic immune-governed feature. Durable aNAb responses against all rebound-competent reservoir variants may be required for functional HIV-1 cure.
SN - 0027-8424
SN - 1091-6490
ER -