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

IgA is the most abundant immunoglobulin in mucosal secretions, and understanding the role of IgA in both protection from HIV acquisition and modulation of HIV disease progression is a field of considerable controversy and renewed research interest. Analysis of the RV144 clinical trial associated plasma HIV envelope-specific monomeric IgA from vaccines with reduced vaccine efficacy. The RV144 trial, however, only assessed for plasma IgA, which was not further subclassed, and the role of mucosal IgA was not addressed as mucosal samples were not collected. On the other hand, several studies have detected envelope-specific IgA in mucosal secretions of highly exposed persistently seronegative cohorts, while recent macaque simian-HIV passive immunization studies have suggested a potentially protective role for mucosal IgA. It is well established that total IgA in serum appears to correlate with HIV disease progression. In contrast, a selective deficit of anti-HIV IgA responses in HIV infection is apparent, with a number of recent studies beginning to elucidate the mechanisms behind these dysfunctional IgA responses. In this review, we highlight the dichotomy that exists in the literature as to whether anti-HIV IgA is protective or harmful to the host. Herein, we emphasize the importance of distinguishing between monomeric, multimeric, and isoforms of IgA and review what is known about the complex and diverse interactions of various molecular forms of IgA with HIV in both the systemic circulation and mucosal compartments.