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Additional IC ligands and their role in HIV.

Gal-9 is a member of the galectin family of animal lectins and binds to the TIM-3 receptor. It has a wide range in biological properties and its role in the context of HIV is complex. Gal-9 is upregulated on NK cells in PWH97 and on CD4+ and CD8+ T-cells with impaired T-cell effector function.98 Gal-9 was also shown to be rapidly released during acute HIV infection with high levels remaining in the circulation even upon viral control with a positive correlation between plasma Gal-9 levels and HIV viral load.99 Furthermore a recent report demonstrated the ability of Gal-9 to reactivate latent HIV-1 in a jurkat T-cell line.52 This finding is consistent with a recent study showing Gal-9 shedding by neutrophils can activate T cells via binding to CD44 which leads to T cell activation in PWH.100 CD155 is a ligand of the TIM-3 receptor and was shown to be upregulated on CD4+ Tfh cells that reside in the lymph node, a major site of HIV persistence.53,56,101 It was suggested that HIV can directly upregulate CD155 cells through a Vpr-dependent mechanism,102 but newer studies challenged these observations.103