HIV-1 Cross-Reactive Primary Virus Neutralizing Antibody Response Elicited by Immunization in Nonhuman Primates

• Published in: Journal of virology 2017-11, Vol.91 (21), p.e00910
• Main Authors: Wang, Yimeng, O'Dell, Sijy, Turner, Hannah L, Chiang, Chi-I, Lei, Lin, Guenaga, Javier, Wilson, Richard, Martinez-Murillo, Paola, Doria-Rose, Nicole, Ward, Andrew B, Mascola, John R, Wyatt, Richard T, Karlsson Hedestam, Gunilla B, Li, Yuxing
• Format: Article
• Language: English
• Subjects: Animals; Antibodies, Neutralizing - immunology; Cells, Cultured; Cross Reactions - immunology; env Gene Products, Human Immunodeficiency Virus - immunology; Epitopes - immunology; HIV Antibodies - immunology; HIV Infections - immunology; HIV Infections - virology; HIV-1 - immunology; Humans; Immunization; Macaca mulatta - immunology; Macaca mulatta - virology; Medicin och hälsovetenskap; Vaccination; Vaccines and Antiviral Agents
• ISSN: 0022-538X; 1098-5514; 1098-5514
• DOI: 10.1128/JVI.00910-17

Elicitation of broadly neutralizing antibody (bNAb) responses is a major goal for the development of an HIV-1 vaccine. Current HIV-1 envelope glycoprotein (Env) vaccine candidates elicit predominantly tier 1 and/or autologous tier 2 virus neutralizing antibody (NAb) responses, as well as weak and/or sporadic cross-reactive tier 2 virus NAb responses with unknown specificity. To delineate the specificity of vaccine-elicited cross-reactive tier 2 virus NAb responses, we performed single memory B cell sorting from the peripheral blood of a rhesus macaque immunized with YU2gp140-F trimers in adjuvant, using JR-FL SOSIP.664, a native Env trimer mimetic, as a sorting probe to isolate monoclonal Abs (MAbs). We found striking genetic and functional convergence of the SOSIP-sorted Ig repertoire, with predominant VH4 or VH5 gene family usage and Env V3 specificity. Of these vaccine-elicited V3-specific MAbs, nearly 20% (6/33) displayed cross-reactive tier 2 virus neutralization, which recapitulated the serum neutralization capacity. Substantial similarities in binding specificity, neutralization breadth and potency, and sequence/structural homology were observed between selected macaque cross-reactive V3 NAbs elicited by vaccination and prototypic V3 NAbs derived from natural infections in humans, highlighting the convergence of this subset of primate V3-specific B cell repertories. Our study demonstrated that cross-reactive primary virus neutralizing B cell lineages could be elicited by vaccination as detected using a standardized panel of tier 2 viruses. Whether these lineages could be expanded to acquire increased breadth and potency of neutralization merits further investigation. Elicitation of antibody responses capable of neutralizing diverse HIV-1 primary virus isolates (designated broadly neutralizing antibodies [bNAbs]) remains a high priority for the vaccine field. bNAb responses were so far observed only in response to natural infection within a subset of individuals. To achieve this goal, an improved understanding of vaccine-elicited responses, including at the monoclonal Ab level, is essential. Here, we isolated and characterized a panel of vaccine-elicited cross-reactive neutralizing MAbs targeting the Env V3 loop that moderately neutralized several primary viruses and recapitulated the serum neutralizing antibody response. Striking similarities between the cross-reactive V3 NAbs elicited by vaccination in macaques and natural infections in humans illu