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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.T he phase III RV144 ALVAC/AIDSVAX B/E HIV-1 vaccine efficacy trial in Thailand demonstrated 31.2% estimated vaccine efficacy through 42 mo of follow-up (1). Analysis of correlates of risk of infection indicated that envelope (Env)-specific plasma antibody responses were associated with a lower infection risk in vaccinees (2). Though plasma Env variable region 1 and 2 (V1/V2) IgG correlated with decreased infection risk, high levels of anti-HIV-1 Env plasma IgA correlated with increased infection risk (2). Interaction analyses demonstrated that, in the presence of low IgA Env antibodies, antibody-dependent cellular cytotoxicity (ADCC) responses inversely correlated with risk of infection, whereas in the presence of high IgA Env plasma antibodies, there was no correlation with risk of infection (2). Because there was no overall enhancement of infection risk in the trial (1), we hypothesized that Env IgA might block potentially protective effector functions of Env IgG antibodies.Antibody function depends, in part, on ability to bind to Fc receptors (FcR) on effector cells. The antibody isotype and subclass influences its affinity for different cellular FcRs (3, 4). IgG antibodies that mediate ADCC through natural killer (NK) cells bind to FcγRIIIa (CD16). In contrast, 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.Here, we examined plasma IgA and monomeric IgA monoclonal antibodies from RV144 vaccine recipients to test the hypothesis that some fraction of the vaccine-elicited IgA response could block IgG-mediated ADCC function. We found that a f...

Most simian–human immunodeficiency viruses (SHIVs) bearing envelope (Env) glycoproteins from primary HIV-1 strains fail to infect rhesus macaques (RMs). We hypothesized that inefficient Env binding to rhesus CD4 (rhCD4) limits virus entry and replication and could be enhanced by substituting naturally occurring simian immunodeficiency virus Env residues at position 375, which resides at a critical location in the CD4-binding pocket and is under strong positive evolutionary pressure across the broad spectrum of primate lentiviruses. SHIVs containing primary or transmitted/founder HIV-1 subtype A, B, C, or D Envs with genotypic variants at residue 375 were constructed and analyzed in vitro and in vivo. Bulky hydrophobic or basic amino acids substituted for serine-375 enhanced Env affinity for rhCD4, virus entry into cells bearing rhCD4, and virus replication in primary rhCD4 T cells without appreciably affecting antigenicity or antibody-mediated neutralization sensitivity. Twenty-four RMs inoculated with subtype A, B, C, or D SHIVs all became productively infected with different Env375 variants—S, M, Y, H, W, or F—that were differentially selected in different Env backbones. Notably, SHIVs replicated persistently at titers comparable to HIV-1 in humans and elicited autologous neutralizing antibody responses typical of HIV-1. Seven animals succumbed to AIDS. These findings identify Env–rhCD4 binding as a critical determinant for productive SHIV infection in RMs and validate a novel and generalizable strategy for constructing SHIVs with Env glycoproteins of interest, including those that in humans elicit broadly neutralizing antibodies or bind particular Ig germ-line B-cell receptors.

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