Journal
NATURE MEDICINE
Volume 21, Issue 11, Pages 1332-1336Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/nm.3963
Keywords
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Funding
- Centre for the AIDS Programme of Research (CAPRISA)
- South African Medical Research Council (MRC) SHIP program
- NIH [AI116086-01]
- Vaccine Research Center
- National Institute of Allergy and Infectious Diseases (NIAID)
- South African HIV/AIDS Research and Innovation Platform of the South African Department of Science and Technology
- US NIAID, NIH, US Department of Health and Human Services grant [U19 AI51794]
- Columbia University-Southern African Fogarty AIDS International Training and Research Program through the Fogarty International Center, NIH [5 D43 TW000231]
- University of the Witwatersrand Postgraduate Merit Award
- Poliomyelitis Research Foundation PhD Bursary
- National Research Foundation of South Africa Innovation PhD Bursary
- National Research Foundation of South Africa
- Wellcome Trust Intermediate Fellowship in Public Health and Tropical Medicine [089933/Z/09/Z]
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The elicitation of broadly neutralizing antibodies (bNAbs) is likely to be essential for a preventative HIV-1 vaccine, but this has not yet been achieved by immunization. In contrast, some HIV-1-infected individuals naturally mount bNAb responses during chronic infection, suggesting that years of maturation may be required for neutralization breadth(1-6). Recent studies have shown that viral diversification precedes the emergence of bNAbs, but the significance of this observation is unknown(7,8). Here we delineate the key viral events that drove neutralization breadth within the CAP256-VRC26 family of 33 monoclonal antibodies (mAbs) isolated from a superinfected individual. First, we identified minority viral variants, termed bNAb-initiating envelopes, that were distinct from both of the transmitted/founder (T/F) viruses and that efficiently engaged the bNAb precursor. Second, deep sequencing revealed a pool of diverse epitope variants (immunotypes) that were preferentially neutralized by broader members of the antibody lineage. In contrast, a 'dead-end' antibody sublineage unable to neutralize these immunotypes showed limited evolution and failed to develop breadth. Thus, early viral escape at key antibody-virus contact sites selects for antibody sublineages 'that Can tolerate these changes, thereby providing a mechanism for the generation of neutralization breadth within a developing antibody lineage.
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