Biological sex impacts multiple aspects of HIV and the immune response. To identify sex-specific pathways relevant to HIV pathogenesis and cure strategies, we performed transcriptional profiling on a cohort of HIV-positive men and women matched on critical virologic and immunologic factors. Data were analyzed to identify genes and pathways differentially expressed by sex, and gene expression was related to virologic parameters.
Peripheral blood was collected from men(n=26) and matched reproductive age women(n=26) on fully suppressive ART. RNA was isolated and sequenced with the 3′ digital gene expression platform (Broad Institute). Transcripts were analyzed for differential expression of genes and with gene set enrichment analysis(GSEA) to identify selectively enhanced pathways. Transcriptional profiles were regressed to measures of HIV persistence (total and integrated HIV DNA and unspliced and multiply spliced RNA) for each sex.
20% of variation in transcriptional profiles is attributable to biological sex (multidimensional scaling analysis). 1429 genes and 16 GSEA pathways were differentially expressed (FDR<0.05). The IFNα(p<0.001, FDR 0.008) and IFNγ(p<0.001, FDR 0.02) pathways were upregulated in women, as seen in HIV uninfected subjects previously. Supervised analysis of interferon pathway genes demonstrated higher expression of antiviral genes (IRF7, ISG15 and MX1) in women. Men and women also showed distinct patterns of inflammasome gene expression with NLRP8, CIITA and NLRC5 upregulated in women; these genes are known to counterbalance pro-inflammatory NLRs. Women and men had distinct transcriptional correlates of HIV reservoir (combined HIV DNA and usRNA). Heme metabolism (anti-inflammatory) and UV response (DNA damage inducer of senescence) pathways positively correlated to the measures of HIV persistence in men. Oxidative response, glycolysis, E2F and Myc pathways (all features of active metabolism and functional T cell responses) were positively correlated with reservoir in women.
HIV-infected men and women on fully suppressive ART have distinct transcriptional profiles. Women show enrichment of antiviral pathways along with genes that counterbalance inflammatory components of the inflammasome. Sex-specific analysis of HIV reservoir correlates identifies different gene pathways in men and women. Biological sex determines distinct transcriptional patterns that are related to HIV reservoir, with sex-specific implications for cure strategies