Abstract
Analysis of correlates of risk of infection in the RV144 HIV-1 vaccine efficacy trial demonstrated that plasma IgG against the HIV-1 envelope (Env) variable region 1 and 2 inversely correlated with risk, whereas HIV-1 Env-specific plasma IgA responses directly correlated with risk. In the secondary analysis, antibody-dependent cellular cytotoxicity (ADCC) was another inverse correlate of risk, but only in the presence of low plasma IgA Env-specific antibodies. Thus, we investigated the hypothesis that IgA could attenuate the protective effect of IgG responses through competition for the same Env binding sites. We report that Env-specific plasma IgA/IgG ratios are higher in infected than in uninfected vaccine recipients in RV144. Moreover, Env-specific IgA antibodies from RV144 vaccinees blocked the binding of ADCC-mediating mAb to HIV-1 Env glycoprotein 120 (gp120). An Env-specific monomeric IgA mAb isolated from an RV144 vaccinee also inhibited the ability of natural killer cells to kill HIV-1-infected CD4(+) T cells coated with RV144-induced IgG antibodies. We show that monomeric Env-specific IgA, as part of postvaccination polyclonal antibody response, may modulate vaccine-induced immunity by diminishing ADCC effector function.
Highlights
Analysis of correlates of risk of infection in the RV144 HIV-1 vaccine efficacy trial demonstrated that plasma IgG against the HIV-1 envelope (Env) variable region 1 and 2 inversely correlated with risk, whereas HIV-1 Env-specific plasma IgA responses directly correlated with risk
We found that a fraction of the HIV-1–specific IgA response was directed against conformational epitopes in the first constant (C1) region of glycoprotein 120, a specificity of RV144 vaccine trial antibodies previously shown to mediate antibody-dependent cellular cytotoxicity (ADCC) via natural killer (NK) cells [5, 6]
We demonstrate that the HIV-1 Env-specific IgA/IgG ratio directly correlated with infection risk, suggesting that for some HIV-1 Env specificities, the balance of Env IgA and Env IgG might influence vaccine efficacy
Summary
Analysis of correlates of risk of infection in the RV144 HIV-1 vaccine efficacy trial demonstrated that plasma IgG against the HIV-1 envelope (Env) variable region 1 and 2 inversely correlated with risk, whereas HIV-1 Env-specific plasma IgA responses directly correlated with risk. Env-specific IgA antibodies from RV144 vaccinees blocked the binding of ADCC-mediating mAb to HIV-1 Env glycoprotein 120 (gp120). IgA antibodies do not bind to FcγRIIIa, but, rather, have high affinity for FcαRI (CD89) expressed by monocytes/macrophages and polymorphonuclear cells (PMN). This differential profile of FcR binding by IgG and IgA antibodies impacts the effector function capabilities of these antibody isotypes. We found that a fraction of the HIV-1–specific IgA response was directed against conformational epitopes in the first constant (C1) region of glycoprotein 120 (gp120), a specificity of RV144 vaccine trial antibodies previously shown to mediate ADCC via NK cells [5, 6]. The RV144 vaccine-elicited polyclonal antibody response included IgA antibodies with specificities that blocked IgG-mediated ADCC
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