Format

Send to

Choose Destination
PLoS Pathog. 2016 Aug 25;12(8):e1005815. doi: 10.1371/journal.ppat.1005815. eCollection 2016 Aug.

Minimally Mutated HIV-1 Broadly Neutralizing Antibodies to Guide Reductionist Vaccine Design.

Jardine JG1,2,3,4, Sok D1,2,3,5, Julien JP2,3,6,7, Briney B1,2,3, Sarkar A2,3,6, Liang CH1,2,3, Scherer EA8, Henry Dunand CJ9, Adachi Y1,2,3,4, Diwanji D6, Hsueh J1,2,3, Jones M1,2,4, Kalyuzhniy O1,2,3,4, Kubitz M1,2,3, Spencer S1,2,3,4, Pauthner M1,2,3, Saye-Francisco KL1,2,3, Sesterhenn F1,2,3, Wilson PC9, Galloway DM8, Stanfield RL2,3,6, Wilson IA2,3,6,10, Burton DR1,2,3,11, Schief WR1,2,3,4,11.

Author information

1
Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, California, United States of America.
2
IAVI Neutralizing Antibody Center, The Scripps Research Institute, La Jolla, California, United States of America.
3
Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery, The Scripps Research Institute, La Jolla, California, United States of America.
4
Department of Biochemistry, University of Washington, Seattle, Washington, United States of America.
5
International AIDS Vaccine Initiative, New York, New York, United States of America.
6
Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, California, United States of America.
7
Program in Molecular Structure and Function, The Hospital for Sick Children Research Institute and Departments of Biochemistry and Immunology, University of Toronto, Toronto, Ontario, Canada.
8
Human Biology Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America.
9
Department of Medicine, Section of Rheumatology, The Knapp Center for Lupus and Immunology Research, The University of Chicago, Chicago, Illinois, United States of America.
10
Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, California, United States of America.
11
Ragon Institute of MGH, MIT, and Harvard, Cambridge, Massachusetts, United States of America.

Abstract

An optimal HIV vaccine should induce broadly neutralizing antibodies (bnAbs) that neutralize diverse viral strains and subtypes. However, potent bnAbs develop in only a small fraction of HIV-infected individuals, all contain rare features such as extensive mutation, insertions, deletions, and/or long complementarity-determining regions, and some are polyreactive, casting doubt on whether bnAbs to HIV can be reliably induced by vaccination. We engineered two potent VRC01-class bnAbs that minimized rare features. According to a quantitative features frequency analysis, the set of features for one of these minimally mutated bnAbs compared favorably with all 68 HIV bnAbs analyzed and was similar to antibodies elicited by common vaccines. This same minimally mutated bnAb lacked polyreactivity in four different assays. We then divided the minimal mutations into spatial clusters and dissected the epitope components interacting with those clusters, by mutational and crystallographic analyses coupled with neutralization assays. Finally, by synthesizing available data, we developed a working-concept boosting strategy to select the mutation clusters in a logical order following a germline-targeting prime. We have thus developed potent HIV bnAbs that may be more tractable vaccine goals compared to existing bnAbs, and we have proposed a strategy to elicit them. This reductionist approach to vaccine design, guided by antibody and antigen structure, could be applied to design candidate vaccines for other HIV bnAbs or protective Abs against other pathogens.

PMID:
27560183
PMCID:
PMC4999182
DOI:
10.1371/journal.ppat.1005815
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Public Library of Science Icon for PubMed Central
Loading ...
Support Center