Vaccine Induction of Heterologous Tier 2 HIV-1 Neutralizing Antibodies in Animal Models

Publication date: 26 December 2017
Source:Cell Reports, Volume 21, Issue 13
Author(s): Kevin O. Saunders, Laurent K. Verkoczy, Chuancang Jiang, Jinsong Zhang, Robert Parks, Haiyan Chen, Max Housman, Hilary Bouton-Verville, Xiaoying Shen, Ashley M. Trama, Richard Scearce, Laura Sutherland, Sampa Santra, Amanda Newman, Amanda Eaton, Kai Xu, Ivelin S. Georgiev, M. Gordon Joyce, Georgia D. Tomaras, Mattia Bonsignori, Steven G. Reed, Andres Salazar, John R. Mascola, M. Anthony Moody, Derek W. Cain, Mireille Centlivre, Sandra Zurawski, Gerard Zurawski, Harold P. Erickson, Peter D. Kwong, S. Munir Alam, Yves Levy, David C. Montefiori, Barton F. Haynes
The events required for the induction of broad neutralizing antibodies (bnAbs) following HIV-1 envelope (Env) vaccination are unknown, and their induction in animal models as proof of concept would be critical. Here, we describe the induction of plasma antibodies capable of neutralizing heterologous primary (tier 2) HIV-1 strains in one macaque and two rabbits. Env immunogens were designed to induce CD4 binding site (CD4bs) bnAbs, but surprisingly, the macaque developed V1V2-glycan bnAbs. Env immunization of CD4bs bnAb heavy chain rearrangement (VHDJH) knockin mice similarly induced V1V2-glycan neutralizing antibodies (nAbs), wherein the human CD4bs VH chains were replaced with mouse rearrangements bearing diversity region (D)-D fusions, creating antibodies with long, tyrosine-rich HCDR3s. Our results show that Env vaccination can elicit broad neutralization of tier 2 HIV-1, demonstrate that V1V2-glycan bnAbs are more readily induced than CD4bs bnAbs, and define VH replacement and diversity region fusion as potential mechanisms for generating V1V2-glycan bnAb site antibodies.

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Teaser

Saunders et al. demonstrate that HIV-1 broadly neutralizing antibodies can be induced by vaccination, albeit only in select animals. Studies in neutralizing antibody variable heavy chain (VH) knockin mice suggest a mechanism for broadly neutralizing antibody induction that involves heavy chain replacement and fusion of immunoglobulin diversity (D) regions.


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