Inhibitory potential of autologous neutralizing antibodies sets quantitative limits on the rebound-competent HIV-1 reservoir
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 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, rather resistance to autologous neutralizing antibodies was a critical determinant of viral rebound. Using inhibitory potential ( <i>IP</i> ), the log reduction in single-round infection at physiologic IgG concentrations, we defined quantitative limits governing rebound-competency. Reservoir variants exhibited a wide range of <i>IP</i> 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 allows previously neutralized variants to gain rebound potential. Thus, rebound competency is a dynamic, immune-governed property defined by quantitative immunologic constraints.
Authors
- Janet D. Siliciano (ORCID: https://orcid.org/0000-0001-6712-3775)
- Thomas Dalhuisen (ORCID: https://orcid.org/0000-0001-9132-0496)
- Dylan H. Westfall (ORCID: https://orcid.org/0000-0002-2434-8525)
- Rebecca Hoh (ORCID: https://orcid.org/0000-0001-5112-4220)
- Lillian B. Cohn (ORCID: https://orcid.org/0000-0002-3485-8692)
- Brianna Lopez (ORCID: https://orcid.org/0000-0001-9254-255X)
- Francesco R. Simonetti (ORCID: https://orcid.org/0000-0002-4165-660X)
- Mauro Garcia (ORCID: https://orcid.org/0000-0002-8520-7144)
- Emily J. Fray (ORCID: https://orcid.org/0000-0002-5850-6237)
- Jun Lai (ORCID: https://orcid.org/0009-0008-6435-2888)
- Michael J. Peluso (ORCID: https://orcid.org/0000-0003-0585-6230)
- Tingting Chu
- Joseph Varriale (ORCID: https://orcid.org/0000-0002-9663-3325)
- Steven G. Deeks (ORCID: https://orcid.org/0000-0001-6371-747X)
- Junlin Zhuo (ORCID: https://orcid.org/0000-0002-5311-6707)
- Haoyue Li
- Robert F. Siliciano (ORCID: https://orcid.org/0000-0002-1764-1993)
- Beril Aydin
- Kirsten J. Sowers
- Anna Farrell-Sherman
- Anthony Abeyta-Lopez
- Donald Lubbeck
- Moonki Chae
- Anna M. Zinsser
Institutions
- Cape Town HVTN Immunology Laboratory / Hutchinson Centre Research Institute of South Africa (ZA)
- Johns Hopkins University (US)
- University of California, San Francisco (US)
- Johns Hopkins Medicine (US)
- Fred Hutch Cancer Center (US)
- University of San Francisco (US)
Publication Details
- Journal
- bioRxiv (Cold Spring Harbor Laboratory)
- Published
- 2025-12-09
- DOI
- https://doi.org/10.64898/2025.12.07.692769
- Primary Topic
- HIV Research and Treatment
- Type
- article
- Field-Weighted Citation Impact
- 0.00