Background
Biological sex plays an important role in HIV progression, including during treatment with combined antiretroviral therapy (cART). Earlier research suggests that men generally have larger viral reservoirs, while women experience a higher risk for HIV-associated cardiovascular disease (CVD). To better understand these differences, we compared the plasma proteome in cART treated men and women living with HIV (MLHIV, WLHIV) and assessed associations with viral reservoir size and comorbidities.
Methods
Targeted plasma proteomics (n = 2,367) was performed in two independent cohorts of cART-treated people living with HIV (PLHIV) from the 2000HIV study (Discovery cohort: 1,232 men, 213 women, Validation cohort: 262 men, 46 women). Associations between plasma proteome and sex were assessed using linear regression. HIV-specificity of the sex-biased differentially abundant proteins (DAPs) was assessed by comparison to DAPs from a population-based study (UK Biobank). Total and intact HIV-1 DNA was measured in circulating CD4 T cells using the digital PCR based 5-region multiplexed Rainbow assay. Associations of sex-specific DAPs with reservoir size and comorbidities were assessed in the 2000HIV cohort. Associations of HIV- and sex-DAPs with prevalent CVD in the UK Biobank were extracted for men and women separately.
Results
We observed 484 differentially abundant proteins (FDRdiscovery < 0.05 & Pvalidation < 0.05) between MLHIV and WLHIV (sex-DAPs), mostly consistent with the UK Biobank. Notably, we identified 24 sex-DAPs only observed in or with reverse direction in PLHIV compared to the general population (HIV- and sex-DAPs). 22 were upregulated in men, some related to NK and T cell function. Of those, CXCL9, KLRD1, and TNFRSF9 were positively associated with HIV-DNA levels in circulating CD4 cells (FDRdiscovery < 0.1 and directionally validated), which were higher in men in the 2000HIV cohort. Additionally, nineteen HIV- and sex-DAPs were associated with CVD in the UK Biobank (FDR < 0.05), with mixed effects on CVD risk. For example, higher VWF and lower ANGPT1 in WLHIV predisposes them to CVD, while lower levels of other proteins (e.g. TNFRSF9, CXCL9 and KLRD1) in WLHIV seems protective.
Conclusions
We identified 24 sex-DAPs unique to PLHIV, some of which suggest increased NK and T cell processes in men, possibly driven by a larger viral reservoir. In addition, some predispose women to CVD, and might represent novel predictive biomarkers and female-specific treatment targets.