A genetic variation in Fucosyltransferase 8 accelerates HIV-1 disease progression indicating a role for N-glycan fucosylation.

OBJECTIVES: Core fucosylation by fucosyltransferase 8 (FUT8) is an important post-translational modification that impacts components of the immune system. Genetic variations in FUT8 can alter its function and could therefore play a role in the anti-viral immune response and pathogenesis of HIV-1. This study analyzed the effect of a single nucleotide polymorphism (SNP) in FUT8 on the clinical course of HIV-1 infection.

DESIGN/METHODS: The effect of SNPs in FUT8 on untreated HIV-1 disease outcome were analyzed in a cohort of 304 people with HIV-1 (PWH) using survival analysis. Flow-cytometry was used to determine the effect of SNP on T-cell activation, differentiation and exhaustion/senescence. T-cell function was determined by proliferation assay and by measuring intracellular cytokine production. The effect of the SNP on HIV-1 replication was determined by in-vitro HIV-1 infections. Sensitivity of HIV-1 produced in PBMC with or without the SNP to broadly neutralizing antibodies was determined using a TZM-bl based neutralization assay.

RESULTS: Presence of the minor allele of SNP rs4131564 was associated with accelerated disease progression. The SNP had no effect on T-cell activation and T cell differentiation in PWH. Additionally, no differences in T cell functionality as determined by proliferation and cytokine production was observed. HIV-1 replication and neutralization sensitivity was also unaffected by the SNP in FUT8.

CONCLUSIONS: SNP rs4131564 in FUT8 showed a major impact on HIV-1 disease course underscoring a role for N-glycan fucosylation even though no clear effect on the immune system or HIV-1 could be determined in vitro.