Human Galectin-9 Promotes the Expansion of HIV Reservoirs in vivo in Humanized Mice

Abstract

ABSTRACTObjectiveThe human endogenous β-galactoside-binding protein Galectin-9 (Gal-9) reactivates latently HIV-infected cells, which may allow for immune-mediated clearance of these cells. However, Gal-9 also activates T cell Receptor (TCR) signaling pathways, which could negatively affect HIV persistence by promoting T cell expansion and chronic activation/exhaustion. This potential “double-edged sword” effect of Gal-9 during HIV infection raises the question of the overall beneficial versus detrimental impact of Gal-9 on HIV persistence in vivo.DesignWe used the BLT (bone marrow, liver, thymus) humanized mouse model to evaluate the overall impact of Gal-9 on HIV persistence in vivo during antiretroviral therapy (ART).MethodsTwo independent cohorts of BLT mice with high human immune reconstitution were infected with HIV, placed on ART, and then treated with either recombinant human Gal-9 or PBS during ART suppression. Plasma viral loads and levels of tissue-associated HIV DNA and RNA were measured by qPCR. Markers of T cell activation/exhaustion were measured by flow cytometry, and plasma markers of inflammation were measured by multiplex cytokine arrays.ResultsGal-9 treatment was tolerable in ART-suppressed humanized mice and did not significantly induce plasma markers of inflammation or T cell markers of activation/exhaustion. However, Gal-9 treatment during ART significantly increased levels of tissue-associated HIV DNA and RNA compared to controls (P=0.0007 and P=0.011, respectively, for cohort I and P=0.002 and P=0.005, respectively, for cohort II).ConclusionsOur study highlights the overall adverse effects of Gal-9 on HIV persistence and the potential need to block Gal-9 interactions during ART-suppressed HIV infection.