Cardiovascular disease (CVD) remains an important comorbidity in people living with HIV-1 (PLWH) receiving antiretroviral therapy (ART). Our previous studies performed in the Canadian HIV/Aging Cohort Study (CHACS) (>40 years-old; Framingham Risk Score (FRS) > 5%) revealed a 2–3-fold increase in non-calcified coronary artery atherosclerosis (CAA) plaque burden, measured by computed tomography angiography scan (CTAScan) as the total (TPV) and low attenuated plaque volume (LAPV), in ART-treated PLWH (HIV+) versus uninfected controls (HIV−). In an effort to identify novel correlates of subclinical CAA, markers of intestinal damage (sCD14, LBP, FABP2); cell trafficking/inflammation (CCL20, CX3CL1, MIF, CCL25); subsets of Th17-polarized and regulatory (Tregs) CD4⁺ T-cells, classical/intermediate/non-classical monocytes, and myeloid/plasmacytoid dendritic cells were studied in relationship with HIV and TPV/LAPV status. The TPV detection/values coincided with higher plasma sCD14, FABP2, CCL20, MIF, CX3CL1, and triglyceride levels; lower Th17/Treg ratios; and classical monocyte expansion. Among HIV⁺, TPV⁺ versus TPV⁻ exhibited lower Th17 frequencies, reduced Th17/Treg ratios, higher frequencies of non-classical CCR9^lowHLADR^high monocytes, and increased plasma fibrinogen levels. Finally, Th17/Treg ratios and non-classical CCR9^lowHLADR^high monocyte frequencies remained associated with TPV/LAPV after adjusting for FRS and HIV/ART duration in a logistic regression model. These findings point to Th17 paucity and non-classical monocyte abundance as novel immunological correlates of subclinical CAA that may fuel the CVD risk in ART-treated PLWH.

Antiretroviral therapy (ART) controls HIV-1 replication in people with HIV-1 (PWH), but intestinal integrity impairment persists and fuels microbial translocation and chronic immune activation, thus heightening the cardiovascular disease (CVD) risk. Here, we sought to identify novel immunological correlates of the HIV and CVD status in ART-treated PWH (HIV⁺; n = 42) and uninfected participants (HIV⁻; n = 40) of the Canadian HIV and Aging Cohort Study (CHACS), with/without subclinical coronary atherosclerotic plaques, measured by Coronary Computed Tomography Angiography as total plaque volume (TPV, mm³). PBMCs were analyzed by flow cytometry for the expression of T-cell lineage (CD45, CD3, CD4, CD8αα, CD8αβ, TCRαβ, TCRγδ), epithelial cell (EpCAM/CD326), activation (HLA-DR), and gut-homing/residency markers (CD69, CD196/CCR6, CD199/CCR9, CD49d/Itgα4, CD103/ItgαE, Itgβ7). Alterations in the CD3⁺ T-cell pool, such as increased frequencies of CD8⁺TCRαβ⁺ and TCRγδ⁺ cells, to the detriment of CD4⁺TCRαβ⁺ subsets, were associated with the HIV status. Also, CD4⁺ T-cells with CD326⁺CD69⁺CCR6⁺ItgαE⁺ and CCR6⁺Itgβ7⁻ phenotypes were increased in frequency in HIV⁺ vs. HIV⁻ participants, together with a decreased frequency of CD8⁺ T-cells with an intraepithelial lymphocyte (IEL)-like CD3⁺CD4⁻TCRαβ⁺TCRγδ⁻CD8αα⁺CD8αβ⁻ phenotype. Finally, multivariate logistic regression identified the frequency of ItgαE⁺CD8⁺, ItgαE⁻CD8⁺, CCR6⁺CD4⁺, and CCR6⁺Itgβ7⁻CD4⁺ T-cells as strong positive correlates of HIV status and atherosclerotic plaque in ART-treated PWH.