Complementary antibody lineages achieve neutralization breadth in an HIV-1 infected elite neutralizer

van Schooten, Jelle; Schorcht, Anna; Farokhi, Elinaz; Umotoy, Jeffrey C.; Gao, Hongmei; van den Kerkhof, Tom M.; Dorning, Jessica; Rijkhold Meesters, Tim G.; van der Woude, Patricia; Burger, Judith A.; Bijl, Tom; Ghalaiyini, Riham; Torrents de la Peña, Alba; Turner, Hannah L.; Labranche, Celia C.; Stanfield, Robyn L.; Sok, Devin; Schuitemaker, Hanneke; Montefiori, David C.; Burton, Dennis R.; Ozorowski, Gabriel; Seaman, Michael S.; Wilson, Ian A.; Sanders, Rogier W.; Ward, Andrew B.; van Gils, Marit J.

doi:10.1371/journal.ppat.1010945

Complementary antibody lineages achieve neutralization breadth in an HIV-1 infected elite neutralizer

Journal Article · Wed Nov 16 23:00:00 EST 2022 · PLoS Pathogens

DOI:https://doi.org/10.1371/journal.ppat.1010945· OSTI ID:2423892

^[1]; Schorcht, Anna ^[1]; Farokhi, Elinaz ^[2]; Umotoy, Jeffrey C. ^[1]; Gao, Hongmei ^[3]; van den Kerkhof, Tom M. ^[1]; Dorning, Jessica ^[4]; Rijkhold Meesters, Tim G. ^[1]; van der Woude, Patricia ^[1]; Burger, Judith A. ^[1]; Bijl, Tom ^[1]; Ghalaiyini, Riham ^[1]; Torrents de la Peña, Alba ^[2]; Turner, Hannah L. ^[2]; Labranche, Celia C. ^[3]; Stanfield, Robyn L. ^[2]; Sok, Devin ^[5]; Schuitemaker, Hanneke ^[1]; Montefiori, David C. ^[3]; Burton, Dennis R. ^[6] more »

Univ. of Amsterdam (Netherlands)
The Scripps Research Inst., La Jolla, CA (United States)
Duke Univ., Durham, NC (United States). Medical Center
Harvard Medical School, Boston, MA (United States)
The Scripps Research Inst., La Jolla, CA (United States); International AIDS Vaccine Initiative, New York, NY (United States)
The Scripps Research Inst., La Jolla, CA (United States); MIT and Harvard, Cambridge, MA (United States). Ragon Institute of MGH
Univ. of Amsterdam (Netherlands); Cornell Univ., New York, NY (United States). Weill Medical College

Broadly neutralizing antibodies (bNAbs) have remarkable breadth and potency against most HIV-1 subtypes and are able to prevent HIV-1 infection in animal models. However, bNAbs are extremely difficult to induce by vaccination. Defining the developmental pathways towards neutralization breadth can assist in the design of strategies to elicit protective bNAb responses by vaccination. Here, HIV-1 envelope glycoproteins (Env)-specific IgG⁺ B cells were isolated at various time points post infection from an HIV-1 infected elite neutralizer to obtain monoclonal antibodies (mAbs). Multiple antibody lineages were isolated targeting distinct epitopes on Env, including the gp120-gp41 interface, CD4-binding site, silent face and V3 region. The mAbs each neutralized a diverse set of HIV-1 strains from different clades indicating that the patient’s remarkable serum breadth and potency might have been the result of a polyclonal mixture rather than a single bNAb lineage. High-resolution cryo-electron microscopy structures of the neutralizing mAbs (NAbs) in complex with an Env trimer generated from the same individual revealed that the NAbs used multiple strategies to neutralize the virus; blocking the receptor binding site, binding to HIV-1 Env N-linked glycans, and disassembly of the trimer. These results show that diverse NAbs can complement each other to achieve a broad and potent neutralizing serum response in HIV-1 infected individuals. Hence, the induction of combinations of moderately broad NAbs might be a viable vaccine strategy to protect against a wide range of circulating HIV-1 viruses.

View Accepted Manuscript (DOE)

Research Organization:: SLAC National Accelerator Laboratory, Menlo Park, CA (United States). Stanford Synchrotron Radiation Lightsource (SSRL)

Sponsoring Organization:: USDOE

Grant/Contract Number:: AC02-76SF00515

OSTI ID:: 2423892

Journal Information:: PLoS Pathogens, Journal Name: PLoS Pathogens Journal Issue: 11 Vol. 18; ISSN 1553-7374

Publisher:: Public Library of ScienceCopyright Statement

Country of Publication:: United States

Language:: English

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Complementary antibody lineages achieve neutralization breadth in an HIV-1 infected elite neutralizer

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