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

doi:10.1016/j.celrep.2018.11.058

V2-Directed Vaccine-like Antibodies from HIV-1 Infection Identify an Additional K169-Binding Light Chain Motif with Broad ADCC Activity

Cell Rep. 2018 Dec 11;25(11):3123-3135.e6. doi: 10.1016/j.celrep.2018.11.058.

Authors

Charmaine van Eeden¹, Constantinos Kurt Wibmer¹, Cathrine Scheepers¹, Simone I Richardson¹, Molati Nonyane², Bronwen Lambson¹, Nonhlanhla N Mkhize¹, Balakrishnan Vijayakumar³, Zizhang Sheng⁴, Sherry Stanfield-Oakley⁵, Jinal N Bhiman¹, Valerie Bekker², Tandile Hermanus², Batsirai Mabvakure¹, Arshad Ismail², M Anthony Moody⁵, Kevin Wiehe⁵, Nigel Garrett⁶, Salim Abdool Karim⁶, Heini Dirr³, Manuel A Fernandes⁷, Yasien Sayed³, Lawrence Shapiro⁸, Guido Ferrari⁵, Barton F Haynes⁵, Penny L Moore⁹, Lynn Morris¹⁰

Affiliations

¹ 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.
² National Institute for Communicable Diseases of the National Health Laboratory Service, Johannesburg 2131, South Africa.
³ Protein Structure-Function Research Unit, University of the Witwatersrand, Johannesburg 2000, South Africa.
⁴ 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.
⁵ Duke Human Vaccine Institute, Duke University, Durham, NC 27710, USA.
⁶ Centre for the AIDS Programme of Research in South Africa (CAPRISA), University of KwaZulu Natal, Durban 4041, South Africa.
⁷ Molecular Sciences Institute, School of Chemistry, University of the Witwatersrand, Johannesburg 2000, South Africa.
⁸ 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.
⁹ 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.
¹⁰ 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. Electronic address: [email protected].

Abstract

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.

Keywords: ADCC; CAP228; CH58; ED motif; HIV; K169; RV144 vaccine response; V2 antibodies; V2 structure; antibody evolution.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

AIDS Vaccines / immunology*
Alleles
Amino Acid Sequence
Antibody-Dependent Cell Cytotoxicity / immunology*
HIV Antibodies / immunology*
HIV Antibodies / isolation & purification
HIV Envelope Protein gp120 / chemistry*
HIV Envelope Protein gp120 / metabolism
HIV Infections / immunology*
HIV Infections / virology*
Humans
Immunoglobulin Light Chains / chemistry
Immunoglobulin Light Chains / metabolism*
Lysine / metabolism*
Models, Molecular
Peptides / metabolism
Protein Binding
Tissue Donors

Substances

AIDS Vaccines
HIV Antibodies
HIV Envelope Protein gp120
Immunoglobulin Light Chains
Peptides
Lysine

Abstract

Publication types

MeSH terms

Substances

Grants and funding