Estrogen's Impact on IgG Glycomic Modulation of Immunity and Inflammation During HIV - Modified PROJECT SUMMARY. Antibodies can trigger a variety of immune responses beyond neutralization, and the glycosylation of antibodies strongly impacts these responses. In our recent publication (Giron et al., Nature Communications, 2024)3, we found that IgGs from people with HIV (PWH) on antiretroviral therapy (ART) exhibit a greater loss of galactose, a glycan associated with younger biological age, than did IgGs from people without HIV. This loss of IgG galactose (agalactosylation) in PWH was associated with higher inflammation, more severe inflammation-associated comorbidities, and larger HIV reservoirs during ART, and faster HIV rebound after ART interruption. In our investigation of a mechanism that can link IgG agalactosylation to these adverse outcomes, we found that agalactosylation reduced the capacity of anti-HIV IgGs to elicit Fc-mediated innate immune functions such as antibody-dependent cell-mediated cytotoxicity. Such impaired anti-viral immune functions can contribute to poor viral control that can lead to higher inflammation. However, whether this HIV- associated IgG agalactosylation and its associated reduction in immune function can be reversed is not known. Sex hormones, particularly estrogen, alter IgG glycosylation. To understand estrogen's impact on IgG glycosylation in PWH on ART, we analyzed samples from women with HIV on ART (WWH) receiving estradiol (E2) and male controls. WWH had lower IgG agalactosylation and higher IgG galactosylation than men with HIV. Notably, the levels of IgG galactosylation in WWH aligned closely with levels of IgG galactosylation in men without HIV. This suggested that estrogen could reverse the HIV-associated loss of IgG galactose, potentially enhancing anti-HIV innate immune functions and reducing HIV active reservoirs and inflammation. Antibody- producing B cells express high levels of estrogen receptors. Estrogen engagement with these receptors modulates B-cell signaling and possibly glycosylation machinery. Given estrogen's role in various immunological functions, understanding the mechanisms behind the estrogen- mediated modulation of IgG glycomes and its downstream impact on anti-viral Fc-mediated innate immune functions, viral reservoir size, and inflammation is crucial. We will investigate these unknowns by testing our overarching hypothesis that estrogen directly modulates the glycosylation machinery of B cells to promote the production of galactosylated antibodies (Aim 1), and these antibodies are more efficient at eliciting anti-viral Fc- mediated innate immune functions, leading to smaller viral reservoirs and lower inflammation (Aim 2). For these studies, we will use an in vitro B cell differentiation system, samples from SIV-infected female rhesus macaques on ART that underwent ovariectomy and received E2, and samples from WWH on ART, before and after E2 treatment. We aim to uncover novel mechanistic links between estrogen, anti-viral immunity, HIV persistence, and inflammation, offering therapeutic insights for PWH, including post-menopausal women.
