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. 2023 Nov 1;37(13):1959-1969.
doi: 10.1097/QAD.0000000000003689. Epub 2023 Aug 17.

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

Lisa van Pul  1   2 , Irma Maurer  1   2 , Brigitte D M Boeser-Nunnink  1   2 , Agnes M Harskamp  1   2 , Karel A van Dort  1   2 , Neeltje A Kootstra  1   2
Affiliations

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

Lisa van Pul et al. AIDS. .

Abstract

Objectives: Core fucosylation by fucosyltransferase 8 (FUT8) is an important posttranslational modification that impacts components of the immune system. Genetic variations in FUT8 can alter its function and could, therefore, play a role in the antiviral immune response and pathogenesis of HIV-1. This study analysed 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 analysed 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.

Conclusion: 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 .

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Conflict of interest statement

There are no conflicts of interest.

Figures

Fig. 1
Fig. 1
The effect of a single nucleotide polymorphism in FUT8 on HIV-1 disease progression, CD4+ T-cell count, viral load at setpoint, T-cell activation and serum sCD163 and iFABP levels.
Fig. 2
Fig. 2
The effect of single nucleotide polymorphism rs4131564 on T-cell differentiation, exhaustion, senescence and proliferation in people with HIV.
Fig. 3
Fig. 3
The effect of single nucleotide polymorphism rs4131564 on polyfunctionality of CD4+ and CD8+ T cells.
Fig. 4
Fig. 4
The effect of single nucleotide polymorphism rs4131564 on viral replication and antibody neutralization.
See this image and copyright information in PMC

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