Rare twin cysteine residues in the HIV-1 envelope variable region 1 link to neutralization escape and breadth development

Maria C Hesselman¹, Marius Zeeb², Peter Rusert¹, Chloé Pasin², Jennifer Mamrosh³, Samuel Kariuki⁴, Ian Pichler¹, Michèle Sickmann¹, Masako M Kaufmann¹, Daniel Schmidt¹, Nikolas Friedrich¹, Karin J Metzner², Audrey Rindler², Herbert Kuster², Craig Adams⁵, Ruwayhida Thebus⁵, Michael Huber¹, Sabine Yerly⁶, Karoline Leuzinger⁷, Matthieu Perreau⁸, Roger Koller⁹, Günter Dollenmaier¹⁰, Simona Frigerio¹¹, Dylan H Westfall¹², Wenjie Deng¹², Allan C deCamp¹³, Michal Juraska¹³, Srilatha Edupuganti¹⁴, Nyaradzo Mgodi¹⁵, Hugh Murrell⁵, Nigel Garrett¹⁶, Kshitij Wagh³, James I Mullins¹², Carolyn Williamson¹⁷, Penny L Moore¹⁸, Huldrych F Günthard², Roger D Kouyos², Alexandra Trkola¹⁹

Affiliations

¹ Institute of Medical Virology, University of Zurich (UZH), 8057 Zurich, Switzerland.
² Institute of Medical Virology, University of Zurich (UZH), 8057 Zurich, Switzerland; Department of Infectious Diseases and Hospital Epidemiology, University Hospital Zurich (USZ), 8091 Zurich, Switzerland.
³ Theoretical Biology and Biophysics Group, Los Alamos National Laboratory, Los Alamos, NM 87545, USA.
⁴ Department of Biological Sciences, School of Science, University of Eldoret, 30100 Eldoret, Kenya; Institute for Infectious Diseases and Molecular Medicine, Division of Medical Virology, Faculty of Health Sciences, University of Cape Town and National Health Laboratory Service, 7925 Cape Town, South Africa.
⁵ Institute for Infectious Diseases and Molecular Medicine, Division of Medical Virology, Faculty of Health Sciences, University of Cape Town and National Health Laboratory Service, 7925 Cape Town, South Africa.
⁶ Laboratory of Virology, University Hospital Geneva, University of Geneva, 1205 Geneva, Switzerland.
⁷ Clinical Virology, University Hospital Basel, 4031 Basel, Switzerland.
⁸ Division of Immunology and Allergy, University Hospital Lausanne, University of Lausanne, 1011 Lausanne, Switzerland.
⁹ Institute for Infectious Diseases, University of Bern, 3001 Bern, Switzerland.
¹⁰ Centre for Laboratory Medicine, 9008 St. Gallen, Switzerland.
¹¹ Institute of Laboratory Medicine, Ente Ospedaliero Cantonale, 6500 Bellinzona, Switzerland.
¹² Department of Microbiology at the University of Washington, Seattle, WA 98195, USA.
¹³ Fred Hutchinson Cancer Center, Seattle, WA 98109, USA.
¹⁴ Department of Medicine, Division of Infectious Diseases, Emory University, Atlanta, GA 30322, USA.
¹⁵ University of Zimbabwe Clinical Trials Research Centre, Harare, Zimbabwe; University of California, San Francisco, San Francisco, CA 94115, USA.
¹⁶ Department of Public Health Medicine, School of Nursing and Public Health, University of KwaZulu-Natal, 4041 Durban, South Africa; Centre for the AIDS Programme of Research in South Africa (CAPRISA), University of KwaZulu-Natal, 4013 Durban, South Africa.
¹⁷ Institute for Infectious Diseases and Molecular Medicine, Division of Medical Virology, Faculty of Health Sciences, University of Cape Town and National Health Laboratory Service, 7925 Cape Town, South Africa; Centre for the AIDS Programme of Research in South Africa (CAPRISA), University of KwaZulu-Natal, 4013 Durban, South Africa.
¹⁸ SA MRC Antibody Immunity Research Unit, School of Pathology, Faculty of Health Sciences, University of the Witwatersrand, 2050 Johannesburg, South Africa; National Institute for Communicable Disease of the National Health Laboratory Services, 2192 Johannesburg, South Africa; Centre for the AIDS Programme of Research in South Africa (CAPRISA), University of KwaZulu-Natal, 4013 Durban, South Africa.
¹⁹ Institute of Medical Virology, University of Zurich (UZH), 8057 Zurich, Switzerland. Electronic address: trkola.alexandra@virology.uzh.ch.

PMID: 39909038
DOI: 10.1016/j.chom.2025.01.004

Free article

Rare twin cysteine residues in the HIV-1 envelope variable region 1 link to neutralization escape and breadth development

Maria C Hesselman et al. Cell Host Microbe. 2025.

Free article

. 2025 Feb 12;33(2):279-293.e6.

doi: 10.1016/j.chom.2025.01.004. Epub 2025 Feb 4.

Authors

Affiliations

¹ Institute of Medical Virology, University of Zurich (UZH), 8057 Zurich, Switzerland.
² Institute of Medical Virology, University of Zurich (UZH), 8057 Zurich, Switzerland; Department of Infectious Diseases and Hospital Epidemiology, University Hospital Zurich (USZ), 8091 Zurich, Switzerland.
³ Theoretical Biology and Biophysics Group, Los Alamos National Laboratory, Los Alamos, NM 87545, USA.
⁴ Department of Biological Sciences, School of Science, University of Eldoret, 30100 Eldoret, Kenya; Institute for Infectious Diseases and Molecular Medicine, Division of Medical Virology, Faculty of Health Sciences, University of Cape Town and National Health Laboratory Service, 7925 Cape Town, South Africa.
⁵ Institute for Infectious Diseases and Molecular Medicine, Division of Medical Virology, Faculty of Health Sciences, University of Cape Town and National Health Laboratory Service, 7925 Cape Town, South Africa.
⁶ Laboratory of Virology, University Hospital Geneva, University of Geneva, 1205 Geneva, Switzerland.
⁷ Clinical Virology, University Hospital Basel, 4031 Basel, Switzerland.
⁸ Division of Immunology and Allergy, University Hospital Lausanne, University of Lausanne, 1011 Lausanne, Switzerland.
⁹ Institute for Infectious Diseases, University of Bern, 3001 Bern, Switzerland.
¹⁰ Centre for Laboratory Medicine, 9008 St. Gallen, Switzerland.
¹¹ Institute of Laboratory Medicine, Ente Ospedaliero Cantonale, 6500 Bellinzona, Switzerland.
¹² Department of Microbiology at the University of Washington, Seattle, WA 98195, USA.
¹³ Fred Hutchinson Cancer Center, Seattle, WA 98109, USA.
¹⁴ Department of Medicine, Division of Infectious Diseases, Emory University, Atlanta, GA 30322, USA.
¹⁵ University of Zimbabwe Clinical Trials Research Centre, Harare, Zimbabwe; University of California, San Francisco, San Francisco, CA 94115, USA.
¹⁶ Department of Public Health Medicine, School of Nursing and Public Health, University of KwaZulu-Natal, 4041 Durban, South Africa; Centre for the AIDS Programme of Research in South Africa (CAPRISA), University of KwaZulu-Natal, 4013 Durban, South Africa.
¹⁷ Institute for Infectious Diseases and Molecular Medicine, Division of Medical Virology, Faculty of Health Sciences, University of Cape Town and National Health Laboratory Service, 7925 Cape Town, South Africa; Centre for the AIDS Programme of Research in South Africa (CAPRISA), University of KwaZulu-Natal, 4013 Durban, South Africa.
¹⁸ SA MRC Antibody Immunity Research Unit, School of Pathology, Faculty of Health Sciences, University of the Witwatersrand, 2050 Johannesburg, South Africa; National Institute for Communicable Disease of the National Health Laboratory Services, 2192 Johannesburg, South Africa; Centre for the AIDS Programme of Research in South Africa (CAPRISA), University of KwaZulu-Natal, 4013 Durban, South Africa.
¹⁹ Institute of Medical Virology, University of Zurich (UZH), 8057 Zurich, Switzerland. Electronic address: trkola.alexandra@virology.uzh.ch.

PMID: 39909038
DOI: 10.1016/j.chom.2025.01.004

Abstract

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.

Keywords: Env stabilization; HIV vaccine; V1V2; broadly neutralizing antibodies; elite neutralizers; envelope glycoprotein.

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Conflict of interest statement

Declaration of interests All authors declare no direct competing interests related to this study, including financial interests, patents, board affiliations, and paid consultant activities.

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Rare twin cysteine residues in the HIV-1 envelope variable region 1 link to neutralization escape and breadth development

Affiliations

Rare twin cysteine residues in the HIV-1 envelope variable region 1 link to neutralization escape and breadth development

Authors

Affiliations

Abstract

Conflict of interest statement

MeSH terms

Substances

LinkOut - more resources

Full Text Sources

Molecular Biology Databases

Miscellaneous