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Nat Med. 2015 Nov;21(11):1332-6. doi: 10.1038/nm.3963. Epub 2015 Oct 12.

Viral variants that initiate and drive maturation of V1V2-directed HIV-1 broadly neutralizing antibodies.

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Centre for HIV and STIs, National Institute for Communicable Diseases (NICD) of the National Health Laboratory Service (NHLS), Johannesburg, South Africa.
Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa.
Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Cape Town, South Africa.
Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.
Department of Biochemistry and Systems Biology, Columbia University, New York, New York, USA.
Centre for the AIDS Programme of Research in South Africa (CAPRISA), University of KwaZulu Natal, Durban, South Africa.
National Health Laboratory Services, Johannesburg, South Africa.


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. Recent studies have shown that viral diversification precedes the emergence of bNAbs, but the significance of this observation is unknown. 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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