OP1-Innate immune dysregulation may be linked to cardiovascular disease risk among adolescents with perinatally acquired HIV on antiretroviral therapy

Abstract

Perinatally-acquired human immunodeficiency virus (PHIV) and antiretroviral therapy (ART) may alter the development and function of the immune system. Evidence suggests that altered immune cells may accelerate aging and increase the risk for future end-organ complications, including cardiovascular disease (CVD).

Objective

This study aimed to identify potential mechanisms by which innate cells contribute to CVD pathology.

Design, setting and methods

In this cross-sectional study, using high-dimensional flow cytometry, biomarker profiling, and transcriptomics, we compared immune signatures in cryopreserved peripheral blood mononuclear cells and cardiovascular biomarkers in Ugandan adolescents with PHIV on ART (n=18) and age/sex-matched HIV-unexposed and uninfected Ugandan adolescents (controls, n=20). The median age was 14 years, 50% were females, and all PHIVs were virally suppressed (HIV-1 RNA<50 copies/mL). Statistical comparisons were performed using the Mann-Whitney U test, with significance set at p < 0.05. We explored the connection between immune signatures and plasma biomarkers using the Pearson correlation coefficient.

Results

Carotid intima-media thickness, a marker of atherosclerosis, was significantly greater among PHIVs compared with HIV-negative controls. Among PHIVs, significantly higher activation/memory/migration marker (CD69⁺, HLA-DR⁺, NKp44⁺, CD57⁺, CXCR3⁺) positive cell percentages were found in many natural killer (NK; CD45⁺CD3^-CD14^-CD56⁺CD16^+/-) cell subsets (i.e., CD56^briCD16^-, CD56^dimCD16^-, CD56^dimCD16^dim). Pro-inflammatory intermediate monocytes (CD14⁺CD16⁺) were significantly increased (as a percentage of total monocytes) in PHIVs. Levels of plasma oxidized LDL were significantly lower among PHIVs compared to controls. Significant negative correlations (r>-0.5) were found between percentages of activated, vascular tissue-homing CCR5+ CD56^briCD16^dim, CD56^dimCD16^- CD56^dimCD16^dim NK subsets and plasma ox-LDL among PHIVs. In vitro studies confirmed a significantly increased uptake of ox-LDL by macrophages in the presence of activated NK cells. Bulk RNA sequencing revealed significant upregulation of genes associated with immune cell migration (CXCL10), cholesterol uptake into tissues (CD36), and vascular remodeling (CD163) (p < 0.05 for all). 

Conclusions

We demonstrate increased percentages of activated/memory-like/migratory NK subsets and pro-inflammatory monocytes with the potential to home to vascular tissue in adolescents with PHIV. We further show that activated NK cells may influence the increased uptake of plasma ox-LDL into vessel wall macrophages, initiating atherogenesis in adolescents with PHIV.

*This work has been previously presented at the 25^th International AIDS Conference (July 2024). A preprint is available online (DOI:10.1101/2023.11.06.23297580).