Background
Mitochondria are crucial for cellular energy metabolism and immune regulation, but their role in spontaneous HIV control remains unclear. We hypothesized that single nucleotide polymorphisms (SNPs) in mitochondrial-related genes influence HIV control.
Methods
SNP-set enrichment analysis was conducted to determine if SNPs in autosomal mitochondrial-related genes are enriched in HIV-control associated SNPs compared to the rest of the genome, using GWAS summary statistics from Europeans in the 2000HIV cohort (NCT03994835). This analysis included 67 HIV controllers and 1,176 non-controllers. Functionally relevant SNPs were prioritized using expression quantitative trait loci (eQTL) data. The effect of prioritized SNP genotypes on gene expression and total HIV reservoir DNA copies/million CD4+ T cells in PBMCs was tested using linear regression. Flow cytometry and single-cell expression data were used to explore immune activation and gene expression at single cell level. Co-expression network and pathway enrichment analyses were performed to explore relationships between prioritized genes and pathways.
Results
SNP-set enrichment analysis revealed significant enrichment in mitochondrial genes associated with HIV control (P<1e-5, Figure 1A). Prioritization with eQTLs identified six independent SNPs and four mitochondrial-related genes. Three independent SNPs near VARS2 (rs4713462, rs28436034, rs9266658) significantly associated with HIV control, higher VARS2 expression, and lower viral reservoirs (P<0.05, Figure 1B). VARS2 expression negatively correlated with total reservoir DNA (P<0.05, R2=0.01) and positively with CD4 counts (P<0.05, R2=0.14). Flow cytometry showed VARS2 expression positively associated with T cell activation (memory subsets) and negatively with granulocyte and monocyte activation. Single-cell expression data showed VARS2 highly expressed in T cells. Co-expression analysis revealed VARS2 co-expressed with genes enriched (P<0.01) in mitochondrial tRNA processing and suppression of pro-inflammatory pathways.
Conclusions
Our findings highlight the role of mitochondrial-related genetic variants affecting VARS2 expression, essential for mitochondrial protein synthesis, in HIV reservoir size and immune pathways in European HIV controllers. VARS2 expression linked to heightened T cell activation, reduced innate immune activation, and lower viral reservoirs. This suggests that higher VARS2 expression promotes effective viral control and a protective role in long-term HIV control.