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.

Broadly neutralizing antibodies suppress post-transcytosis HIV-1 infectivity

“…[51][52][53] Importantly, no mechanistic evidence has yet been produced showing that dimeric IgAs in complex with virions form large ''aggregates'' that lead to blocking HIV-1 entry at mucosal sites as hypothesized by others. 58 It is possible, however, that through interaction of IgG/IgA with gelforming mucin glycoproteins in vivo, HIV-antibody complexes get trapped in mucus layers, 59,60 and subsequently get washed out by draining, genital secretions. The inefficacy of potent bNAbs in diminishing viral transepithelial migration is on the other hand, contrasting with the blocking capacity on transcytosis that was previously reported for some gp160specific antibodies, especially for IgAs.…”

Vaccine with bacterium‐like particles displaying HIV‐1 gp120 trimer elicits specific mucosal responses and neutralizing antibodies in rhesus macaques

“…It is necessary to find an effective anti‐HIV‐1 strategy to impede HIV transmission at the mucosal level (Tudor et al ., 2009). Eliciting an efficient immune response including sIgA or neutralizing IgG to block the viral adherence to the epithelial cells, prevent transcytosis and neutralize the viruses in epithelial cells is the desirable goal of a mucosal vaccine design (Huang et al ., 2005; Zhou and Ruprecht, 2014). Preclinical research showed that passively administered bNAbs can protect macaques from the SHIV challenge even with different relative potency (Pegu et al ., 2014).…”

The Multifaceted Nature of Immunoglobulin A and Its Complex Role in HIV

“…The high variability of published findings regarding IgA quantitation is likely also influenced by the lack of standardized assays to measure HIV-binding mucosal IgA antibodies and the significant variation in mucosal sampling and purification techniques. [122][123][124] Immunoassays to detect IgA binding to monomeric envelope proteins may not reliably capture functional antibodies targeted to the native HIV virus envelope. Furthermore, lack of antibody HIV-inhibitory activity could indicate that other HIV-independent factors may be involved in host protection.…”