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

Duke University Medical Center, Durham, North Carolina, USA.
Journal of Virology (Impact Factor: 4.44). 08/2012; 86(21):11521-32. DOI: 10.1128/JVI.01023-12
Source: PubMed


The 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.

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Available from: Daniel M Kozink, Oct 04, 2015
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    • "We isolated antibodies from immunized monkeys utilizing antigen-specific memory B cell sorts with fluorophore-labeled AE.A244 gp120 (Bonsignori et al., 2012) or similarly labeled AE.A244 V1V2 tags protein (Liao et al., 2013) (Figure 1). A total of 39 antibodies were isolated that bound to the V2 region of Env ( 165 LRDKKQKVHALFYKLDIVPIED 186 ) in ELISA assays from NHP studies 36 and 62.1 (Tables S1 and S2). "
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    ABSTRACT: In HIV-1, the ability to mount antibody responses to conserved, neutralizing epitopes is critical for protection. Here we have studied the light chain usage of human and rhesus macaque antibodies targeted to a dominant region of the HIV-1 envelope second variable (V2) region involving lysine (K) 169, the site of immune pressure in the RV144 vaccine efficacy trial. We found that humans and rhesus macaques used orthologous lambda variable gene segments encoding a glutamic acid-aspartic acid (ED) motif for K169 recognition. Structure determination of an unmutated ancestor antibody demonstrated that the V2 binding site was preconfigured for ED motif-mediated recognition prior to maturation. Thus, light chain usage for recognition of the site of immune pressure in the RV144 trial is highly conserved across species. These data indicate that the HIV-1 K169-recognizing ED motif has persisted over the diversification between rhesus macaques and humans, suggesting an evolutionary advantage of this antibody recognition mode. Copyright © 2014 Elsevier Inc. All rights reserved.
    Immunity 12/2014; 41(6):909-918. DOI:10.1016/j.immuni.2014.11.014 · 21.56 Impact Factor
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    • "While desirable, broadly neutralizing, potent Abs that carry long CDR H3 regions and display extreme mutation rates from germline (as reviewed in Mascola and Haynes, 2013) have not yet been induced by any immunization regimen and, as demonstrated by RV144, are not necessarily needed to reduce infection risk. Therefore, the results of RV144 support a targeted effort to improve the design of immunogens such as those used in RV144, as well as recombinant epitope-scaffold immunogens to be used in prime-boost regimens that will induce conventional Abs now shown to be correlates of reduced risk of infection (Bonsignori et al., 2012; Haynes et al., 2012; Gottardo et al., 2013; Zolla-Pazner et al., 2014). "
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    ABSTRACT: To evaluate the role of V3-specific IgG antibodies (Abs) in the RV144 clinical HIV vaccine trial, which reduced HIV-1 infection by 31.2%, the anti-V3 Ab response was assessed. Vaccinees' V3 Abs were highly cross-reactive with cyclic V3 peptides (cV3s) from diverse virus subtypes. Sieve analysis of CRF01_AE breakthrough viruses from 43 vaccine- and 66 placebo-recipients demonstrated an estimated vaccine efficacy of 85% against viruses with amino acids mismatching the vaccine at V3 site 317 (p=0.004) and 52% against viruses matching the vaccine at V3 site 307 (p=0.004). This analysis was supported by data showing vaccinees' plasma Abs were less reactive with I(307) replaced with residues found more often in vaccinees' breakthrough viruses. Simultaneously, viruses with mutations at F(317) were less infectious, possibly due to the contribution of F(317) to optimal formation of the V3 hydrophobic core. These data suggest that RV144-induced V3-specific Abs imposed immune pressure on infecting viruses and inform efforts to design an HIV vaccine.
    11/2014; 1(1):37-45. DOI:10.1016/j.ebiom.2014.10.022
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    • "Moreover, Yates et al. recently found that vaccine-induced HIV-1-specific IgG3 responses correlated with decreased risk of infection in RV144 clinical trial compared to the VAX003 vaccine regimen (82). Since partial protection observed in the RV144 phase III Thailand trial was mediated by the induction of non-neutralizing antibodies (NNAbs) and a moderate T cell response (27, 83), it seems that other immune mechanisms in addition to classical NAbs responses are required to achieve protection against HIV infection. "
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    ABSTRACT: HIV antibody (Ab) functions capable of preventing mucosal cell-free or cell-to-cell HIV transmission are critical for the development of effective prophylactic and therapeutic vaccines. In addition to CD4(+) T cells, other potential HIV-target cell types including antigen-presenting cells (APCs) (dendritic cells, macrophages) residing at mucosal sites are infected. Moreover, the interactions between APCs and HIV lead to HIV cell-to-cell transmission. Recently discovered broadly neutralizing antibodies (NAbs) are able to neutralize a broad spectrum of HIV strains, inhibit cell-to-cell transfer, and efficiently protect from infection in the experimentally challenged macaque model. However, the 31% protection observed in the RV144 vaccine trial in the absence of detectable NAbs in blood samples pointed to the possible role of additional Ab inhibitory functions. Increasing evidence suggests that IgG Fcγ receptor (FcγR)-mediated inhibition of Abs present at the mucosal site may play a role in protection against HIV mucosal transmission. Moreover, mucosal IgA Abs may be determinant in protection against HIV sexual transmission. Therefore, defining Ab inhibitory functions that could lead to protection is critical for further HIV vaccine design. Here, we review different inhibitory properties of HIV-specific Abs and discuss their potential role in protection against HIV sexual transmission.
    Frontiers in Immunology 06/2014; 5:289. DOI:10.3389/fimmu.2014.00289
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