HIV immunological non-responders show low SKAP1 concentration and DNA hypermethylation in the SKAP1 promotor region

OBJECTIVE: The aim of this study was to improve understanding of biological pathways underlying inadequate CD4+ T-cell restoration after initiating antiretroviral treatment as these so called Immunological non-responders are at increased risk for morbidity and mortality while treatment options are lacking. DESIGN: We compared baseline multi-omics data from 88 Immunological non-responders and 1467 immunological responders that participated in the 2000HIV study, separated into a discovery and validation cohort. METHODS: We measured expression levels of 2367 plasma proteins, comparing the immunological responders and non-responders. As this highlighted low Src kinase-associated phosphoprotein 1 (SKAP1) levels in Immunological non-responders, we measured intracellular SKAP1 levels in CD4+ T-cells, investigated DNA methylation and assessed single-nucleotide polymorphisms (SNPs). We also explored whether HIV or CMV infection may influence SKAP1 expression. RESULTS: SKAP1 plasma levels were significantly lower in Immunological non-responders in both cohorts. SKAP1 plasma concentrations reflected intracellular levels in CD4+ T-cells. DNA methylation analysis showed significant hypermethylation at the SKAP1 promotor region. Three SNPs close to the SKAP1 gene were associated with poor Immunological response. Preliminary data suggest that HIV or CMV may influence SKAP1 levels. CONCLUSION: Our data show decreased SKAP1 concentrations in immunological non-responders, potentially driven by hypermethylation of the SKAP1 promoter. Downregulation of SKAP1, which is known to play a role in T cell proliferation and migration, may therefore contribute to the poor restoration of CD4 cell counts after ART.