Rare twin cysteine residues in the HIV-1 envelope variable region 1 link to neutralization escape and breadth development
Identifying HIV-1 envelope (Env) traits associated with neutralization cross-reactivity is crucial for vaccine design. Variable loops 1 and 2 (V1V2), positioned at the Env trimer apex, are key regions linked to neutralization. We describe non-canonical cysteine (Cys) residues in V1 that are enriched in individuals with elite neutralization breadth. Analyzing over 65,000 V1 sequences from the CATNAP database, AMP trials, and longitudinal HIV-1 cohorts (SHCS, ZPHI, and CAPRISA), we found that Env variants with extra V1 Cys are present at low levels and fluctuate over time. Extra V1 Cys associate with elite plasma neutralization, and two additional Cys are preferred, suggesting stabilization through disulfide bonds. Among 34 broadly neutralizing antibody (bnAb)-inducer Envs, 17.6% had elongated V1 regions with extra Cys. These extra Cys moderately increased neutralization resistance and altered bnAb epitope accessibility. Collectively, altering epitope exposure alongside Env stabilization renders the V1 twin Cys motif a promising feature for HIV-1 bnAb immunogens.
Authors
- Nyaradzo Mgodi (ORCID: https://orcid.org/0000-0002-3085-5259)
- Peter Rusert (ORCID: https://orcid.org/0000-0002-1139-8347)
- Michal Juraska (ORCID: https://orcid.org/0000-0002-0920-2915)
- Nigel Garrett (ORCID: https://orcid.org/0000-0002-4530-234X)
- Nikolas Friedrich (ORCID: https://orcid.org/0000-0003-0694-657X)
- Michèle Sickmann
- Ian Pichler (ORCID: https://orcid.org/0009-0002-6303-1544)
- Srilatha Edupuganti (ORCID: https://orcid.org/0000-0001-6566-9969)
- Samuel Mundia Kariuki (ORCID: https://orcid.org/0000-0001-9039-7184)
- Marius Zeeb (ORCID: https://orcid.org/0000-0001-6822-1473)
- Sabine Yerly (ORCID: https://orcid.org/0000-0003-1668-696X)
- Karoline Leuzinger
- Dylan H. Westfall (ORCID: https://orcid.org/0000-0002-2434-8525)
- James I. Mullins (ORCID: https://orcid.org/0000-0002-4461-8158)
- Penny L. Moore (ORCID: https://orcid.org/0000-0001-8719-4028)
- Allan C. deCamp (ORCID: https://orcid.org/0000-0003-1404-4322)
- Herbert Kuster (ORCID: https://orcid.org/0000-0001-6873-0091)
- Matthieu Perreau (ORCID: https://orcid.org/0000-0003-2110-2244)
- Carolyn E. Williamson (ORCID: https://orcid.org/0000-0003-0125-1226)
- Hugh Murrell (ORCID: https://orcid.org/0000-0002-6185-9885)
- Karin J. Metzner (ORCID: https://orcid.org/0000-0003-4862-1503)
- Kshitij Wagh
- Craig Adams
- Chloé Pasin (ORCID: https://orcid.org/0000-0001-8730-790X)
- Huldrych F. Günthard (ORCID: https://orcid.org/0000-0002-1142-6723)
- Alexandra Trkola (ORCID: https://orcid.org/0000-0003-1013-876X)
- Daniel Schmidt (ORCID: https://orcid.org/0000-0002-0655-654X)
- Maria C. Hesselman (ORCID: https://orcid.org/0000-0003-4858-6920)
- Michael Huber (ORCID: https://orcid.org/0000-0002-0384-0000)
- Audrey Rindler (ORCID: https://orcid.org/0000-0002-6976-2623)
- Roger D. Kouyos (ORCID: https://orcid.org/0000-0002-9220-8348)
- Ruwayhida Thebus
- Wenjie Deng (ORCID: https://orcid.org/0000-0002-7846-1101)
- Roger Koller (ORCID: https://orcid.org/0000-0002-8502-9704)
- Simona Frigerio
- Jennifer Mamrosh
- G Dollenmaier
- Masako M. Kaufmann
Institutions
- National Health Laboratory Service (ZA)
- University of Bern (CH)
- Los Alamos National Laboratory (US)
- Emory University (US)
- University of Washington (US)
- University of Zurich (CH)
- University of St.Gallen (CH)
- University of Eldoret (KE)
- Centre for the AIDS Programme of Research in South Africa (ZA)
- University Hospital of Basel (CH)
- Fred Hutch Cancer Center (US)
- Ente Ospedaliero Cantonale (CH)
- University Hospital of Zurich (CH)
- University Hospital of Geneva (CH)
- University of Zimbabwe-University of California San Francisco (ZW)
- Institute of Virology of the Slovak Academy of Sciences (SK)
- University of Lausanne (CH)
Publication Details
- Journal
- Cell Host & Microbe
- Published
- 2025-02-01
- DOI
- https://doi.org/10.1016/j.chom.2025.01.004
- Citations
- 2
- Primary Topic
- HIV Research and Treatment
- Type
- article
- Field-Weighted Citation Impact
- 2.07
Funders
- National Science Foundation
- Bill and Melinda Gates Foundation
- Novartis Foundation
- National Research Foundation
- South African Medical Research Council
- Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung
- Consiglio Nazionale delle Ricerche
- Novartis Stiftung für Medizinisch-Biologische Forschung
- Universität Zürich
- National Institutes of Health
- Medical Research Council