Diverse specificity and effector function among human antibodies to HIV-1 envelope glycoprotein epitopes exposed by CD4 binding

Abstract

The HIV-1 envelope glycoprotein (Env) undergoes conformational transitions consequent to CD4 binding and coreceptor engagement during viral entry. The physical steps in this process are becoming defined, but less is known about their significance as targets of antibodies potentially protective against HIV-1 infection. Here we probe the functional significance of transitional epitope exposure by characterizing 41 human mAbs specific for epitopes exposed on trimeric Env after CD4 engagement. These mAbs recognize three epitope clusters: cluster A, the gp120 face occluded by gp41 in trimeric Env; cluster B, a region proximal to the coreceptor-binding site (CoRBS) and involving the V1/V2 domain; and cluster C, the coreceptor-binding site. The mAbs were evaluated functionally by antibody-dependent, cell-mediated cytotoxicity (ADCC) and for neutralization of Tiers 1 and 2 pseudoviruses. All three clusters included mAbs mediating ADCC. However, there was a strong potency bias for cluster A, which harbors at least three potent ADCC epitopes whose cognate mAbs have electropositive paratopes. Cluster A epitopes are functional ADCC targets during viral entry in an assay format using virionsensitized target cells. In contrast, only cluster C contained epitopes that were recognized by neutralizing mAbs. There was significant diversity in breadth and potency that correlated with epitope fine specificity. In contrast, ADCC potency had no relationship with neutralization potency or breadth for any epitope cluster. Thus, Fcmediated effector function and neutralization coselect with specificity in anti-Env antibody responses, but the nature of selection is distinct for these two antiviral activities.

Influence of the Envelope gp120 Phe 43 Cavity on HIV-1 Sensitivity to Antibody-Dependent Cell-Mediated Cytotoxicity Responses

“…infected individuals and to mediate potent ADCC responses (13,14,18,(20)(21)(22)(23)(24)(25)(26). Therefore, our results raise the intriguing possibility that histidine 375 present in the predominant strain replicating in Thailand might have contributed to the efficacy of the trial by spontaneously exposing epitopes recognized by ADCC-mediating antibodies elicited by the RV144 vaccine regimen.…”

“…The gp120 outer-domain-specific 2G12 and the anti-gp41 10e8 antibodies were obtained from the NIH AIDS and Research and Reference Reagent Program. Anti-gp120 cluster A antibody A32 and coreceptor binding site antibody 17b were previously reported (14,24,54,55). A32-blockable conformational epitope ADCC-mediating antibodies isolated from recipients of the RV144 ALVAC-HIV AIDSVAX B/E vaccine (CH29, CH38, CH40, CH51, CH52, CH54, CH77, CH80, CH81, CH89, CH91, and CH94) were previously described (14,26).…”

“…Accordingly, we recently reported that the transition of Env to the CD4-bound conformation is required for efficient interactions with ADCC-mediating antibodies (14). We reported that the replacement of serine 375 by a tryptophan residue (S375W) enhanced the exposure of epitopes recognized by anti-cluster A antibodies, known to mediate potent ADCC responses (13,14,18,(20)(21)(22)(23)(24)(25)(26). Thus, the transition of Env from the unbound to the CD4-bound conformation appears to be a prerequisite for the exposure of inner-domain ADCC epitopes.…”

Antibody functional assays as measures of Fc receptor-mediated immunity to HIV - new technologies and their impact on the HIV vaccine field.

“…A high-dose SHIV162P3 challenge study showed that immunisation with gp120-CD4 fusion protein (FLSC) elicited titres of CD4i specific Abs [38], in particular coreceptor binding site specific antibodies [39] that correlated with control of viremia. In what is a presumably more physiological repeated low dose challenge of animals vaccinated across varied FLSC/adjuvant regimens, protection from acquisition was correlated with CD4i antibody and ADCC activity, but only in individuals with low CD4 T cell responses.…”

“…Target cells may also be sensitised using inactivated virus [38]. Standard natural cytotoxicity assays assays measure the release of chromium, 51 Cr, from isotope-labelled unosponised target cells in the presence of NK cells.…”