Polyclonal B Cell Responses to Conserved Neutralization Epitopes in a Subset of HIV-1-Infected Individuals

Abstract

A small proportion of HIV-infected individuals generate a neutralizing antibody (NAb) response of exceptional magnitude and breadth. A detailed analysis of the critical epitopes targeted by broadly neutralizing antibodies should help to define optimal targets for vaccine design. HIV-1-infected subjects with potent cross-reactive serum neutralizing antibodies were identified by assaying sera from 308 subjects against a multiclade panel of 12 "tier 2" viruses (4 each of subtypes A, B, and C). Various neutralizing epitope specificities were determined for the top 9 neutralizers, including clade A-, clade B-, clade C-, and clade A/C-infected donors, by using a comprehensive set of assays. In some subjects, neutralization breadth was mediated by two or more antibody specificities. Although antibodies to the gp41 membrane-proximal external region (MPER) were identified in some subjects, the subjects with the greatest neutralization breadth targeted gp120 epitopes, including the CD4 binding site, a glycan-containing quaternary epitope formed by the V2 and V3 loops, or an outer domain epitope containing a glycan at residue N332. The broadly reactive HIV-1 neutralization observed in some subjects is mediated by antibodies targeting several conserved regions on the HIV-1 envelope glycoprotein.

Deconstructing the Antiviral Neutralizing-Antibody Response: Implications for Vaccine Development and Immunity

“…5A and B) (228). The observation that the antiflavivirus immune response is focused on just a few specificities aligns with data from recent studies on HIV-1, in which some (255)(256)(257)(258) but not all (259)(260)(261)(262) analyses of polyclonal sera with broadly neutralizing activity suggest that just one to two specificities can recapitulate the breadth and potency of the overall serum neutralizing activity. Follow-up studies with multiple strains from each DENV serotype will be needed to explore the fine specificity of serotype-specific NAbs.…”

An autoreactive antibody from an SLE/HIV-1 individual broadly neutralizes HIV-1

“…We interpret the disproportionate frequency of short LCDR1s among CD4bs BnAbs as being indicative of a common selection process of CD4bs BnAbs that favors antibodies with shortened LCDR1s. This is the first chronically infected SLE individual with concomitant HIV-1 infection that we have been able to study, and it was striking that this individual also had robust plasma BnAb activity, given that the incidence of chronically HIV-1-infected subjects with this level of plasma neutralization breadth is only approximately 20% (49)(50)(51)(52).…”

Antibody‐virus co‐evolution in HIV infection: paths for HIV vaccine development

“…Algorithms based on common patterns of neutralizing activity against panels of diverse Env strains are available, that can rapidly estimate whether a new bnAb targets a known epitope (75–79). Often times the epitope can be confirmed by testing neutralizing activity against mutant strains that contain known bnAb-specific diagnostic escape mutations (80, 81). Moreover, computational analyses of Env sequences and corresponding patterns of bnAb activity have been used to identify genetic signatures within and outside bnAb epitopes that compliment crystal structure information in guiding novel immunogen designs (82, 83) (Korber, Hraber, Wagh and Hahn, this volume).…”