Are anti-HIV IgAs good guys or bad guys?

Abstract

An estimated 90% of all HIV transmissions occur mucosally. Immunoglobulin A (IgA) molecules are important components of mucosal fluids. In a vaccine efficacy study, in which virosomes displaying HIV gp41 antigens protected most rhesus monkeys (RMs) against simian-human immunodeficiency virus (SHIV), protection correlated with vaginal IgA capable of blocking HIV transcytosis in vitro. Furthermore, vaginal IgG exhibiting virus neutralization and/or antibody-dependent cellular cytotoxicity (ADCC) correlated with prevention of systemic infection. In contrast, plasma IgG had neither neutralizing nor ADCC activity. More recently, a passive mucosal immunization study provided the first direct proof that dimeric IgAs (dIgAs) can prevent SHIV acquisition in RMs challenged mucosally. This study compared dimeric IgA1 (dIgA1), dIgA2, or IgG1 versions of a human neutralizing monoclonal antibody (nmAb) targeting a conserved HIV Env epitope. While the nmAb neutralization profiles were identical in vitro, dIgA1 was significantly more protective in vivo than dIgA2. Protection was linked to a new mechanism: virion capture. Protection also correlated with inhibition of transcytosis of cell-free virus in vitro. While both of these primate model studies demonstrated protective effects of mucosal IgAs, the RV144 clinical trial identified plasma IgA responses to HIV Env as risk factors for increased HIV acquisition. In a secondary analysis of RV144, plasma IgA decreased the in vitro ADCC activity of vaccine-induced, Env-specific IgG with the same epitope specificity. Here we review the current literature regarding the potential of IgA – systemic as well as mucosal – in modulating virus acquisition and address the question whether anti-HIV IgA responses could help or harm the host.

Humoral Antibody Responses to HIV Viral Proteins and to CD4 Among HIV Controllers, Rapid and Typical Progressors in an HIV-Positive Patient Cohort

“…46,47 In the Thai trial, they recovered high affinity IgA anti-gp120 antibodies from vaccinees and the investigators were able to demonstrate the predicted competition with IgG. 45,48 However, these antibodies were generated in response to vaccination and it is unclear whether such responses are relevant in a natural infection.…”

Antibody-mediated immune exclusion of HIV

“…Of note, RM DNA – unlike human DNA – only encodes one IgA isotype, a molecule that resembles the human IgA2 with its short, Y-shaped hinge region (reviewed in [4*]). The various RM b12 versions were administered i.v., which yielded high plasma concentrations in all monkeys, except that monomeric IgA was rapidly cleared from the circulation [40].…”

“…These data conclusively linked IgA to antigen retention in the mucosal lumen. Subsequent work by different groups has identified antibody (Ab)-mediated immune exclusion as an important mechanism to protect the host against various mucosal pathogens (reviewed in [2*–4*]).…”

“…The latter contains the secretory component (SC) and can exist in higher-order multimers. Dimeric SIgA represents the predominant IgA form in mucosal fluids (reviewed in [4*]).…”

Engineering broadly neutralizing antibodies for HIV prevention and therapy

“…The role of IgA in HIV infection remains controversial [191], with findings of HIV-specific mucosal IgA in exposed but uninfected subjects [94–97] supporting a potentially protective role of mucosal IgA in HIV infection while associations of HIV-specific plasma IgA with increased risk of infection in a vaccine trial [110] suggest a negative role in protection. Passive transfer studies in macaques allowing for more systematic and controlled evaluation of antibody Fc/dose/localization and route of viral challenge clarify the protective potential of mucosal IgA: intrarectal administration of dimeric IgA1 (dIgA1) afforded greater protection from intrarectal viral challenge than dimeric IgA2 or IgG1 bearing the same neutralizing Fv [192], and the combination of intravenous IgG1 with mucosal administration of dIgA1 demonstrated superior protection to either antibody alone [193].…”