Antiretroviral therapy (ART) has demonstrated efficacy and durability in suppressing HIV replication in infected individuals. However, ART does not achieve viral eradication due to the persistence of latently infected cells. The eradication of HIV necessitates elimination of this reservoir. Methods to reactivate HIV latently infected cells allowing direct viral cytopathic effects or immune-mediated clearance are being considered as cure strategies. However, existing latency-reversing agents exert weak effects on HIV reactivation. Alternate biological methods to purge the viral reservoir are needed. Recent reports suggest that the lectin protein, galectin-9, plays an important role in HIV pathogenesis through regulation of both adaptive and innate defense mechanisms. Our preliminary findings have demonstrated that recombinant galectin-9 strongly reactivates latent HIV in vitro and ex vivo, possibly through selective inhibition of histone deacetylases (HDACs) 1, 2 and 3. Biological factors such as galectin-9 that modulate HIV latency may provide an advantage over synthetic agents currently being pursued to reactivate latent HIV. In Aim 1 of this proposal, we hypothesize that endogenous levels of soluble galectin-9 play a significant role in determining the size of the HIV reservoir during suppressive therapy. We will address this hypothesis by measuring plasma levels of galectin-9 in 72 well-characterized HIV-infected individuals on suppressive ART. We will evaluate associations between levels of soluble galectin-9 and previously-generated measurements of virologic and immunologic correlates of HIV reservoir size. In Aim 2, we hypothesize that recombinant galectin-9 strongly reactivates latent HIV ex vivo by inhibiting the activity of HDACs 1, 2 and 3. Primary CD4+ T cells derived from HIV-infected, ART-suppressed individuals will be used to investigate the effects of galectin-9 on viral reactivation, viral production, HDAC protein levels, and classical markers of cellular activation. This proposal will yield valuable insights into the usage of galectin-9 as a foundation for novel HIV cure strategies.