V2-Directed Vaccine-like Antibodies from HIV-1 Infection Identify an Additional K169-Binding Light Chain Motif with Broad ADCC Activity
Charmaine van Eeden,
Constantinos Kurt Wibmer,
Cathrine Scheepers,
Simone I. Richardson,
Molati Nonyane,
Bronwen Lambson,
Nonhlanhla N. Mkhize,
Balakrishnan Vijayakumar,
Zizhang Sheng,
Sherry Stanfield-Oakley,
Jinal N. Bhiman,
Valerie Bekker,
Tandile Hermanus,
Batsirai Mabvakure,
Arshad Ismail,
M. Anthony Moody,
Kevin Wiehe,
Nigel Garrett,
Salim Abdool Karim,
Heini Dirr,
Manuel A. Fernandes,
Yasien Sayed,
Lawrence Shapiro,
Guido Ferrari,
Barton F. Haynes,
Penny L. Moore,
Lynn Morris
Affiliations
Charmaine van Eeden
National Institute for Communicable Diseases of the National Health Laboratory Service, Johannesburg 2131, South Africa; Faculty of Health Sciences, University of the Witwatersrand, Johannesburg 2000, South Africa
Constantinos Kurt Wibmer
National Institute for Communicable Diseases of the National Health Laboratory Service, Johannesburg 2131, South Africa; Faculty of Health Sciences, University of the Witwatersrand, Johannesburg 2000, South Africa
Cathrine Scheepers
National Institute for Communicable Diseases of the National Health Laboratory Service, Johannesburg 2131, South Africa; Faculty of Health Sciences, University of the Witwatersrand, Johannesburg 2000, South Africa
Simone I. Richardson
National Institute for Communicable Diseases of the National Health Laboratory Service, Johannesburg 2131, South Africa; Faculty of Health Sciences, University of the Witwatersrand, Johannesburg 2000, South Africa
Molati Nonyane
National Institute for Communicable Diseases of the National Health Laboratory Service, Johannesburg 2131, South Africa
Bronwen Lambson
National Institute for Communicable Diseases of the National Health Laboratory Service, Johannesburg 2131, South Africa; Faculty of Health Sciences, University of the Witwatersrand, Johannesburg 2000, South Africa
Nonhlanhla N. Mkhize
National Institute for Communicable Diseases of the National Health Laboratory Service, Johannesburg 2131, South Africa; Faculty of Health Sciences, University of the Witwatersrand, Johannesburg 2000, South Africa
Balakrishnan Vijayakumar
Protein Structure-Function Research Unit, University of the Witwatersrand, Johannesburg 2000, South Africa
Zizhang Sheng
Department of Biochemistry and Molecular Biophysics, Columbia University, New York, NY 10027, USA; Department of Systems Biology, Zukerman Mind Brain Behavior Institute, Columbia University, New York, NY 10027, USA
Sherry Stanfield-Oakley
Duke Human Vaccine Institute, Duke University, Durham, NC 27710, USA
Jinal N. Bhiman
National Institute for Communicable Diseases of the National Health Laboratory Service, Johannesburg 2131, South Africa; Faculty of Health Sciences, University of the Witwatersrand, Johannesburg 2000, South Africa
Valerie Bekker
National Institute for Communicable Diseases of the National Health Laboratory Service, Johannesburg 2131, South Africa
Tandile Hermanus
National Institute for Communicable Diseases of the National Health Laboratory Service, Johannesburg 2131, South Africa
Batsirai Mabvakure
National Institute for Communicable Diseases of the National Health Laboratory Service, Johannesburg 2131, South Africa; Faculty of Health Sciences, University of the Witwatersrand, Johannesburg 2000, South Africa
Arshad Ismail
National Institute for Communicable Diseases of the National Health Laboratory Service, Johannesburg 2131, South Africa
M. Anthony Moody
Duke Human Vaccine Institute, Duke University, Durham, NC 27710, USA
Kevin Wiehe
Duke Human Vaccine Institute, Duke University, Durham, NC 27710, USA
Nigel Garrett
Centre for the AIDS Programme of Research in South Africa (CAPRISA), University of KwaZulu Natal, Durban 4041, South Africa
Salim Abdool Karim
Centre for the AIDS Programme of Research in South Africa (CAPRISA), University of KwaZulu Natal, Durban 4041, South Africa
Heini Dirr
Protein Structure-Function Research Unit, University of the Witwatersrand, Johannesburg 2000, South Africa
Manuel A. Fernandes
Molecular Sciences Institute, School of Chemistry, University of the Witwatersrand, Johannesburg 2000, South Africa
Yasien Sayed
Protein Structure-Function Research Unit, University of the Witwatersrand, Johannesburg 2000, South Africa
Lawrence Shapiro
Department of Biochemistry and Molecular Biophysics, Columbia University, New York, NY 10027, USA; Vaccine Research Center, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD 20892-9806, USA
Guido Ferrari
Duke Human Vaccine Institute, Duke University, Durham, NC 27710, USA
Barton F. Haynes
Duke Human Vaccine Institute, Duke University, Durham, NC 27710, USA
Penny L. Moore
National Institute for Communicable Diseases of the National Health Laboratory Service, Johannesburg 2131, South Africa; Faculty of Health Sciences, University of the Witwatersrand, Johannesburg 2000, South Africa; Centre for the AIDS Programme of Research in South Africa (CAPRISA), University of KwaZulu Natal, Durban 4041, South Africa
Lynn Morris
National Institute for Communicable Diseases of the National Health Laboratory Service, Johannesburg 2131, South Africa; Faculty of Health Sciences, University of the Witwatersrand, Johannesburg 2000, South Africa; Centre for the AIDS Programme of Research in South Africa (CAPRISA), University of KwaZulu Natal, Durban 4041, South Africa; Corresponding author
Summary: Antibodies that bind residue K169 in the V2 region of the HIV-1 envelope correlated with reduced risk of infection in the RV144 vaccine trial but were restricted to two ED-motif-encoding light chain genes. Here, we identify an HIV-infected donor with high-titer V2 peptide-binding antibodies and isolate two antibody lineages (CAP228-16H/19F and CAP228-3D) that mediate potent antibody-dependent cell-mediated cytotoxicity (ADCC). Both lineages use the IGHV5-51 heavy chain germline gene, similar to the RV144 antibody CH58, but one lineage (CAP228-16H/19F) uses a light chain without the ED motif. A cocrystal structure of CAP228-16H bound to a V2 peptide identified a IGLV3-21 gene-encoded DDxD motif that is used to bind K169, with a mechanism that allows CAP228-16H to recognize more globally relevant V2 immunotypes. Overall, these data further our understanding of the development of cross-reactive, V2-binding, antiviral antibodies and effectively expand the human light chain repertoire able to respond to RV144-like immunogens. : V2-directed antibodies from the RV144 vaccine trial correlated with reduced HIV-1 infection risk but exhibited restricted light chain gene usage. Here, van Eeden et al. isolate similar antibodies from an HIV-1-infected individual and identify a third V2-reactive light chain gene, increasing the antibody repertoire potentially elicited by vaccination. Keywords: HIV, V2 antibodies, K169, V2 structure, ED motif, CAP228, CH58, antibody evolution, ADCC, RV144 vaccine response
