Centers and Institutes
Published August 25, 2016 | Version v1
Journal article Open

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

Creators

  • 1. Scripps Research Institute
  • 2. Fred Hutchinson Cancer Research Center
  • 3. University of Chicago

Description

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.

Data availability

Coordinates and structure factors have been deposited with the Protein Data Bank for the two crystal structures reported in this manuscript: (1) eOD-N276Kif + VRC01 (PDB ID: 5KZC) and (2) BG505 SOSIP + PGT122 + NIH45-46 (PDB ID: 5D9Q). All other relevant data are within the paper and its Supporting Information files.

Files

journal.ppat.1005815.pdf

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Additional details

Identifiers

DOI
10.1371/journal.ppat.1005815
Other
oai:uchicago.tind.io:6855

Funding

International AIDS Vaccine Initiative Neutralizing Antibody Consortium and Center
Bill and Melinda Gates Foundation
CAVD award
Bayer Science and Education Foundation
National Institute of Allergy and Infectious Diseases
P01AI081625
National Institute of Allergy and Infectious Diseases
CHAVI-ID 1UM1 AI100663
National Institute of Allergy and Infectious Diseases
P01 AI110657
National Institute of Allergy and Infectious Diseases
R01 AI084817
Department of Energy
DE-AC02-06CH11357
NCI
Y1-CO-1020
NIGMS
Y1-GM-1104

UChicago Information

Division(s)
Biological Sciences Division
Department(s)
Medicine
Center(s) or Institute(s)
Gwen Knapp Center for Lupus and Immunology Research