Boosting of Markers of Fc gamma Receptor Function in Anti-HIV Antibodies During Structured Treatment Interruption

Anti-HIV envelope (Env) antibodies elicit important Fc receptor functions, including Fc gamma RIIIa-mediated natural killer cell killing of opsonized infected targets. How these antibodies evolve during HIV infection and treatment remains poorly understood. We describe changes in anti-HIV Env IgG using longitudinal samples from seroconverter subjects treated soon after infection and later during periods of structured treatment interruption (STI). Our well-validated dimeric rsFc gamma R binding assays combine effects of opsonizing antibody subclasses, epitopes, and geometries to provide a measure of Fc gamma R (Fc gamma receptor)-mediated functionality. IgG1 anti-Env titers diminished rapidly during antiretroviral therapy (ART; t(1/2) 3.0 +/- 0.8 months), while the dimeric rsFc gamma RIIIa activity persisted longer (t(1/2) 33 +/- 11 months), suggesting that there is maintenance of functional antibody specificities within the diminished pool of anti-HIV Env Abs. The initial antibody response to infection in two subjects was characterized by approximately fivefold higher Fc gamma RIIIa compared with Fc gamma RIIa binding activity. Uncoupling of Fc gamma RIIa and Fc gamma RIIIa activities may be a distinct feature of the early antibody response that preferentially engages Fc gamma RIIIa-mediated effector functions. Two to three STI cycles, even with low viremia, were sufficient to boost dimeric Fc gamma R activity in these seroconverter subjects. We hypothesize that increased humoral immunity induced by STI is a desirable functional outcome potentially achievable by therapeutic immunization during ART. We conclude that controlled viral antigen exposure under the protection of suppressive ART may be effective in eliciting Fc gamma R-dependent function in support of viral reactivation and kill strategies.