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Staged induction of HIV-1 glycan-dependent broadly neutralizing antibodies. 2017
Mattia Bonsignori, and
Edward F Kreider, and
Daniela Fera, and
R Ryan Meyerhoff, and
Todd Bradley, and
Kevin Wiehe, and
S Munir Alam, and
Baptiste Aussedat, and
William E Walkowicz, and
Kwan-Ki Hwang, and
Kevin O Saunders, and
Ruijun Zhang, and
Morgan A Gladden, and
Anthony Monroe, and
Amit Kumar, and
Shi-Mao Xia, and
Melissa Cooper, and
Mark K Louder, and
Krisha McKee, and
Robert T Bailer, and
Brendan W Pier, and
Claudia A Jette, and
Garnett Kelsoe, and
Wilton B Williams, and
Lynn Morris, and
John Kappes, and
Kshitij Wagh, and
Gift Kamanga, and
Myron S Cohen, and
Peter T Hraber, and
David C Montefiori, and
Ashley Trama, and
Hua-Xin Liao, and
Thomas B Kepler, and
M Anthony Moody, and
Feng Gao, and
Samuel J Danishefsky, and
John R Mascola, and
George M Shaw, and
Beatrice H Hahn, and
Stephen C Harrison, and
Bette T Korber, and
Barton F Haynes
Department of Medicine, Duke University School of Medicine, Duke University Medical Center, Durham, NC 27710, USA. mattia.bonsignori@dm.duke.edu btk@lanl.gov barton.haynes@dm.duke.edu.
A preventive HIV-1 vaccine should induce HIV-1-specific broadly neutralizing antibodies (bnAbs). However, bnAbs generally require high levels of somatic hypermutation (SHM) to acquire breadth, and current vaccine strategies have not been successful in inducing bnAbs. Because bnAbs directed against a glycosylated site adjacent to the third variable loop (V3) of the HIV-1 envelope protein require limited SHM, the V3-glycan epitope is an attractive vaccine target. By studying the cooperation among multiple V3-glycan B cell lineages and their coevolution with autologous virus throughout 5 years of infection, we identify key events in the ontogeny of a V3-glycan bnAb. Two autologous neutralizing antibody lineages selected for virus escape mutations and consequently allowed initiation and affinity maturation of a V3-glycan bnAb lineage. The nucleotide substitution required to initiate the bnAb lineage occurred at a low-probability site for activation-induced cytidine deaminase activity. Cooperation of B cell lineages and an improbable mutation critical for bnAb activity defined the necessary events leading to breadth in this V3-glycan bnAb lineage. These findings may, in part, explain why initiation of V3-glycan bnAbs is rare, and suggest an immunization strategy for inducing similar V3-glycan bnAbs.
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R Ryan Meyerhoff, and
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Kevin Wiehe, and
S Munir Alam, and
Baptiste Aussedat, and
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Krisha McKee, and
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Thomas B Kepler, and
M Anthony Moody, and
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