Differential V2-directed antibody responses in non-human primates infected with SHIVs or immunized with diverse HIV vaccines

Svenja Weiss,Lynn Morris,Susan Zolla-Pazner,Vincenza Itri,Christina C Luo,Ann J Hessell,Xiang-Peng Kong,Nancy L Haigwood,Delphine C Malherbe,Jeff Alexander,Xunqing Jiang,Philip Barnette,Ralf Duerr,Ruimin Pan

doi:10.1038/s41467-022-28450-1

Abstract

V2p and V2i antibodies (Abs) that are specific for epitopes in the V1V2 region of the HIV gp120 envelope (Env) do not effectively neutralize HIV but mediate Fc-dependent anti-viral activities that have been correlated with protection from, or control of HIV, SIV and SHIV infections. Here, we describe a novel molecular toolbox that allows the discrimination of antigenically and functionally distinct polyclonal V2 Ab responses. We identify different patterns of V2 Ab induction by SHIV infection and three separate vaccine regimens that aid in fine-tuning an optimized immunization protocol for inducing V2p and V2i Abs. We observe no, or weak and sporadic V2p and V2i Abs in non-vaccinated SHIV-infected NHPs, but strong V2p and/or V2i Ab responses after immunization with a V2-targeting vaccine protocol. The V2-focused vaccination is superior to both natural infection and to immunization with whole Env constructs for inducing functional V2p- and V2i-specific responses. Strikingly, levels of V2-directed Abs correlate inversely with Abs specific for peptides of V3 and C5. These data demonstrate that a V1V2-targeting vaccine has advantages over the imprecise targeting of SIV/SHIV infections and of whole Env-based immunization regimens for inducing a more focused functional V2p- and V2i-specific Ab response.

Highlights

V2p and V2i antibodies (Abs) that are specific for epitopes in the V1V2 region of the HIV gp[120] envelope (Env) do not effectively neutralize HIV but mediate Fc-dependent anti-viral activities that have been correlated with protection from, or control of HIV, SIV and SHIV infections
RV144 volunteers indicated that the only primary, independent correlate of reduced risk (CoR) was a robust level of nonneutralizing Abs binding to a recombinant protein containing the first and second variable regions (V1V2) of gp[120], a domain in the envelope (Env) glycoprotein of HIV-12–4
V2-specific monoclonal Abs (mAbs) distinguish between HIV-1 Env peptides, proteins, and V1V2-scaffold proteins. To assess their antigenic nature, three gp[120] proteins, five cyclic V2 peptides, three linear V2 peptides[56], and eleven V1V2-fusion proteins were tested for reactivity with five V2p, four V2i, one V2q, and one V2qt-specific mAbs

Summary

Introduction

V2p and V2i antibodies (Abs) that are specific for epitopes in the V1V2 region of the HIV gp[120] envelope (Env) do not effectively neutralize HIV but mediate Fc-dependent anti-viral activities that have been correlated with protection from, or control of HIV, SIV and SHIV infections. The V2-focused vaccination is superior to both natural infection and to immunization with whole Env constructs for inducing functional V2p- and V2i-specific responses. Levels of V2-directed Abs correlate inversely with Abs specific for peptides of V3 and C5. These data demonstrate that a V1V2-targeting vaccine has advantages over the imprecise targeting of SIV/SHIV infections and of whole Env-based immunization regimens for inducing a more focused functional V2p- and V2i-specific Ab response. Later experiments demonstrated a significant inverse CoR with binding to V2 peptides[5] These studies generated the hypothesis that Abs directed against V1V2 contributed to the reduced incidence in HIV infections in vaccinees[1,2,3,4,6]. The RV144 CoR with V1V2 Abs has been buttressed by similar conclusions emanating from several studies of immunized NHPs in which protection, control, and/

Methods

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Conclusion