Galectin-8 binds HIV envelope glycoproteins with high affinity and promotes viral infectivity.

Target cell entry of HIV-1 is dependent on the binding of gp120, the outer component of the viral envelope glycoprotein complex (Env), to CD4 and a coreceptor, preferentially CCR5 or CXCR4. Still, other interactions may also contribute to the infectivity of the virus. One such interaction is between the highly glycosylated gp120 and carbohydrate-binding proteins, such as galectins. Here, we studied the interaction between HIV-1 Env and a panel of galectins and found that galectin-8 (Gal-8), bound with highest affinity (KD < 1µM) and also interacted with soluble CD4. Detailed analysis using probes for different parts of Gal-8 revealed that it was primarily the N-terminal carbohydrate recognition domain that interacted with HIV-1 Env expressing sialylated galactosides and both N- and O-linked glycans. Importantly, in cell cultures Gal-8 enhanced the infectivity of HIV-1, including strains with different coreceptor use and subtype origin, as well as HIV-2. This Gal-8 infectivity enhancement was particularly strong (up to 100-fold) at low virus inoculum doses. Next, we compared Gal-8 infectivity enhancement of primary HIV-1 isolates from people living with HIV at different stages of the infection. Of note, the infectivity of HIV-1 isolates obtained during the chronic, relatively immunocompetent phase, was significantly more enhanced by Gal-8 than isolates obtained at late-stage disease during severe immunodeficiency. Taken together, this study reveals novel carbohydrate dependent interactions between Gal-8 and HIV-1 Env, resulting in enhanced infectivity of HIV-1, with particularly strong effects at low dose exposure of strains circulating during the chronic infection phase. These results suggest that Gal-8 is a cell attachment protein that HIV-1 utilizes for optimized infectivity, which may guide the development of novel intervention strategies targeting this interaction.