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

Article (PDF Available)inJournal of Virology 86(21):11521-32 · August 2012with85 Reads
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
    • "Analysis of the correlates of protection in the RV144 vaccine trial suggested that decreased HIV-1 acquisition was linked to increased ADCC activity in protected vaccinees (Haynes et al., 2012). Accordingly, potent ADCC-mediating antibodies (Abs) targeting anti-cluster A epitopes were isolated from some RV144 vaccinees (Bonsignori et al., 2012) and were shown to preferentially recognize the HIV-1 envelope glycoproteins (Env) in their CD4-bound conformation (Veillette et al., 2014b ). The CD4- bound Env conformation is also recognized by non-neutralizing CD4-in- duced (CD4i) ADCC-mediating antibodies present in sera ( Richard et al., 2015; Richard et al., 2016; Williams et al., 2015), breast milk (Richard et al., 2015) and cervicovaginal lavages (Batraville et al., 2014; Richard et al., 2015 ) of HIV-1-infected individuals . "
    [Show abstract] [Hide abstract] ABSTRACT: HIV-1 developed sophisticated strategies to conceal vulnerable epitopes of its envelope glycoproteins (Env) recognized by antibody-dependent cellular cytotoxicity (ADCC)-mediating antibodies. CD4-mimetics (CD4mc) were shown to sensitize HIV-1-infected cells to ADCC induced by HIV + sera. Here we show that this response requires a sequential opening of Env at the surface of HIV-1-infected cells. Co-receptor binding site antibodies, also present in HIV + sera, are required to expose ADCC-mediating epitopes recognized by anti-cluster A antibodies upon CD4mc addition. The understanding of the conformational changes required to expose anti-cluster A epitopes might be important in the design of new strategies aimed at fighting HIV-1.
    Full-text · Article · Sep 2016
    • "Subsequent analyses showed that non-neutralizing antibodies to variable loops 1 and 2 (V1V2) regions of HIV-1 Env were associated with a reduced risk of HIV-1 acquisition [12 ,15] , and a genetic sieve analysis demonstrated that the ALVAC-HIV/AIDSVAX B/E regimen had improved efficacy against viruses that matched the immunogen sequence in the V2 location [15]. Moreover, high levels of antibody-dependent cellular cytotoxicity (ADCC) were also shown to correlate with a reduced risk of HIV-1 acquisition in RV144 [36] and V2-specific monoclonal antibodies isolated from RV144 vaccines were shown to mediate ADCC against HIV-1-infected CD4+ T cells [37]. HIV-1 specific IgG3 responses were also noted to correlate with protection in RV144 and distinguish this trial from the VAX003 trial [13]. "
    [Show abstract] [Hide abstract] ABSTRACT: With 2 million people newly infected with HIV-1 in 2014, an effective HIV-1 vaccine remains a major public health priority. HIV-1 vaccine efficacy trials in humans, complemented by active and passive immunization studies in non-human primates, have identified several key vaccine-induced immunological responses that may correlate with protection against HIV-1 infection. Potential correlates of protection in these studies include V2-specific, polyfunctional, and broadly neutralizing antibody responses, as well as effector memory T cell responses. Here we review how these correlates of protection are guiding current approaches to HIV-1 vaccine development. These approaches include improvements on the ALVAC-HIV/AIDSVAX B/E vaccine regimen used in the RV144 clinical trial in Thailand, adenovirus serotype 26 vectors with gp140 boosting, intravenous infusions of bNAbs, and replicating viral vectors.
    Full-text · Article · Aug 2016
    • "The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. in alum [7]. The modest reduction of acquisition of HIV infection is thought to correlate with non-neutralizing antibodies, most likely associated with antibody-dependent cellular cytotoxicity (ADCC) [8][9][10]. The HIVIS/TaMoVac consortium has optimized the delivery of multisubtype HIV-DNA and HIV-MVA vaccine candidates in a series of trials, and have shown them to be safe and potent T-cell and B-cell immunogens [11][12][13][14][15]. "
    [Show abstract] [Hide abstract] ABSTRACT: A vaccine against HIV is widely considered the most effective and sustainable way of reducing new infections. We evaluated the safety and impact of boosting with subtype C CN54rgp140 envelope protein adjuvanted in glucopyranosyl lipid adjuvant (GLA-AF) in Tanzanian volunteers previously given three immunizations with HIV-DNA followed by two immunizations with recombinant modified vaccinia virus Ankara (HIV-MVA).
    Full-text · Article · May 2016
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