Modulation of Galectin-9 to Target HIV Persistence

PROJECT SUMMARY While the advent of antiretroviral therapy (ART) has dramatically reduced the morbidity and mortality associated with HIV infection, viral eradication is not achievable due to the persistence of latently-infected cells during treatment. Accumulating data suggest that HIV-infected individuals often experience persistent immune dysregulation, chronic inflammation, and accelerated aging even in the setting of ART-mediated viral suppression. These realities have created a pronounced interest in developing strategies to eradicate or functionally cure HIV infection. Recent work from our group and others has demonstrated a highly important and pleiotropic role of human galectin-9 (Gal-9), an immunoregulatory β-galactoside-binding lectin, in HIV persistence. We have demonstrated that administration of Gal-9 potently reactivates latent HIV in CD4+ T cells, by signaling through specific glycans on the target cell surface. We have additionally revealed that Gal-9 expression in tissues (e.g. CNS) spatially overlaps with HIV infection, and high levels of endogenous, circulating Gal-9 in plasma are strongly associated with long-term maintenance of intact HIV proviral DNA in the CD4+ T cell compartment during ART. Moreover, our recent studies in HIV-infected humanized mice have revealed that exogenously administered Gal-9 significantly increases tissue-associated HIV DNA and RNA levels. In this study, we will comprehensively determine if therapeutic inhibition of Gal-9 signaling at the time of ART initiation can accelerate clearance of the latent HIV reservoir, resolve HIV-associated inflammation, and prevent viral rebound following ART cessation. These goals are well aligned with the stated objective of PAR-23-297. In Aim 1 of our study, we will use established ex vivo latency models to elucidate the molecular and immunologic mechanisms underlying Gal-9-mediated expansion of the HIV reservoir. In Aim 2, we will determine how manipulation (supplementation or blockade) of Gal-9 signaling impacts the HIV reservoir and viral rebound kinetics post-ART cessation in vivo. Our multidisciplinary investigative team at Vitalant Research Institute / UCSF, Weill Cornell Medicine, and Yale University brings a diverse systems biology approach to investigate the impact of Gal-9 on HIV persistence, including tools developed by our group to manipulate Gal-9 signaling in vitro and in vivo (recombinant, stable form exogenous Gal-9, and a panel of anti-Gal-9 monoclonal antibodies that interfere with its virologic effects). Our translational design will leverage carefully designed ex vivo models of HIV persistence, clinical samples from people living with HIV (PLWH) on suppressive ART, and two complementary murine models of HIV latency. Our findings will guide the development of novel HIV cure strategies that leverage the immunomodulatory activities of host galectins.