Antibody-Dependent Cellular Cytotoxicity-Mediating Antibodies from an HIV-1 Vaccine Efficacy Trial Target Multiple Epitopes and Preferentially Use the VH1 Gene Family

Abstract

iThe ALVAC-HIV/AIDSVAX-B/E RV144 vaccine trial showed an estimated efficacy of 31%. RV144 secondary immune correlate analysis demonstrated that the combination of low plasma anti-HIV-1 Env IgA antibodies and high levels of antibody-dependent cellular cytotoxicity (ADCC) inversely correlate with infection risk. One hypothesis is that the observed protection in RV144 is partially due to ADCC-mediating antibodies. We found that the majority (73 to 90%) of a representative group of vaccinees displayed plasma ADCC activity, usually (96.2%) blocked by competition with the C1 region-specific A32 Fab fragment. Using memory B-cell cultures and antigen-specific B-cell sorting, we isolated 23 ADCC-mediating nonclonally related antibodies from 6 vaccine recipients. These antibodies targeted A32-blockable conformational epitopes (n ‫؍‬ 19), a non-A32-blockable conformational epitope (n ‫؍‬ 1), and the gp120 Env variable loops (n ‫؍‬ 3). Fourteen antibodies mediated cross-clade target cell killing. ADCC-mediating antibodies displayed modest levels of V-heavy (VH) chain somatic mutation (0.5 to 1.5%) and also displayed a disproportionate usage of VH1 family genes (74%), a phenomenon recently described for CD4-binding site broadly neutralizing antibodies (bNAbs). Maximal ADCC activity of VH1 antibodies correlated with mutation frequency. The polyclonality and low mutation frequency of these VH1 antibodies reveal fundamental differences in the regulation and maturation of these ADCC-mediating responses compared to VH1 bNAbs.

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.…”

“…A correlation between high levels of ADCC-mediating antibodies and HIV-1 acquisition in the RV144 vaccine trial was suggested for a subset of individuals with low plasma IgA anti-Env antibody levels (26,28). ADCC-mediating MAbs targeting multiple epitopes were isolated from memory B cells of RV144 vaccine recipients (26,38). Importantly, we demonstrated that the vaccine-induced ADCC-mediating antibodies directed against A32-blockable conformational epitopes poorly recognize Env on the surface of HIV-1-infected cells (clade B) unless the CD4 receptor was present on the surface of infected cells.…”

“…A correlation between high levels of ADCC-mediating antibodies and HIV-1 acquisition in the RV144 vaccine trial was suggested for a subset of individuals with low plasma IgA anti-Env antibody levels (26,28). ADCC-mediating MAbs targeting multiple epitopes were isolated from memory B cells of RV144 vaccine recipients (26,38).…”

“…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). Sera from HIV-infected individuals (Table 1) were collected, heat inactivated, and stored as previously described (18).…”

“…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.…”