Journal
CELL
Volume 161, Issue 6, Pages 1280-1292Publisher
CELL PRESS
DOI: 10.1016/j.cell.2015.05.007
Keywords
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Categories
Funding
- Vaccine Research Center, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health
- Division of AIDS, NIAID, National Institutes of Health [AI037526, AI072529, AI0678501, P01 AI094419, P01 AI100148, P01 AI104722, 1UM1 AI100663, UM1 AI100645]
- Howard Hughes Medical Institute
- Bill and Melinda Gates Foundation [38637, 1040753]
- International AIDS Vaccine Initiative's (IAVI's) Neutralizing Antibody Consortium
- US Department of Energy, Basic Energy Sciences, Office of Science [W-31-109-Eng-38]
- Ministry of Foreign Affairs of Denmark
- Irish Aid
- Ministry of Finance of Japan
- Ministry of Foreign Affairs of the Netherlands
- Norwegian Agency for Development Cooperation (NORAD)
- UK Department for International Development (DFID)
- United States Agency for International Development (USAID)
- MRC [G0000635] Funding Source: UKRI
- Medical Research Council [G0000635] Funding Source: researchfish
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The site on the HIV-1 gp120 glycoprotein that binds the CD4 receptor is recognized by broadly reactive antibodies, several of which neutralize over 90% of HIV-1 strains. To understand how antibodies achieve such neutralization, we isolated CD4-binding-site (CD4bs) antibodies and analyzed 16 co-crystal structures -8 determined here- of CD4bs antibodies from 14 donors. The 16 antibodies segregated by recognition mode and developmental ontogeny into two types: CDR H3-dominated and V-H-gene-restricted. Both could achieve greater than 80% neutralization breadth, and both could develop in the same donor. Although paratope chemistries differed, all 16 gp120-CD4bs antibody complexes showed geometric similarity, with antibody-neutralization breadth correlating with antibody-angle of approach relative to the most effective antibody of each type. The repertoire for effective recognition of the CD4 supersite thus comprises antibodies with distinct paratopes arrayed about two optimal geometric orientations, one achieved by CDR H3 ontogenies and the other achieved by V-H-gene-restricted ontogenies.
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