Guenaga J, Wang Y, Wilson R, Lei L, Ward AB, O'Dell S, Karlsson Hedestam GB, Martinez-Murillo P, Chiang CI, Li Y, Wyatt RT, Mascola JR, Doria-Rose N, Turner HL
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 predominantly elicit 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 sorting probe to isolate monoclonal Abs (MAbs). We found striking genetic and functional convergence of the SOSIP-sorted Ig repertoire, with pre-dominant 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.IMPORTANCE Elicitation of antibody responses capable of neutralizing diverse HIV-1 primary virus isolates (designated as broadly neutralizing antibodies, bNAbs) remains a high priority for the vaccine field. bNAb responses were so far only observed in response to natural infection and only in 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 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 illustrate commonalities between the vaccine- and infection-induced responses to V3 and support the feasibility of exploring the V3 epitope as HIV-1 vaccine target in non-human primates.