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.
Highlights
Mucosal secretions represent the first line of defense to protect a host against invasion of viral pathogens, including Human immunodeficiency virus (HIV)
To differentiate between IgA1 and IgA2 versions of the various forms of Immunoglobulin A (IgA), monoclonal antibodies are commercially available that show a high degree of specificity for either human IgA subclass
Among rhesus monkeys (RMs) passively immunized with dimeric IgA1 (dIgA1), 83% were protected compared to only 17% of those given dIgA2 (P = 0.045)
Summary
Mucosal secretions represent the first line of defense to protect a host against invasion of viral pathogens, including HIV. Dimeric or polymeric IgA molecules are important components of mucosal fluids; IgA is present in vaginal and rectal secretions, in saliva, gastric fluid, tears, sweat and in colostrum as well as mature milk. Human IgA has two closely related subclasses, termed IgA1 and IgA2; the major difference between these two lies in the hinge region (Table 1). As a consequence of their open hinge region, IgA1 molecules have a T-like shape, in which the distance between Fab fragments measures approximately. The major IgA form is secretory IgA (SIgA). It is generated from dimeric (dIgA) secreted locally from mature mucosal plasma cells; dIgA consists of two IgA monomers linked covalently via their Fc portions to the joining (J) chain. The open hinge region in SIgA1 makes this molecule more susceptible than SIgA2 to proteolytic
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