HIV Infection Drives Foam Cell Formation via NLRP3 Inflammasome Activation

Abstract

Persistent immune activation is linked to an increased risk of cardiovascular disease (CVD) in people with HIV (PWH) on antiretroviral therapy (ART). The NLRP3 inflammasome may contribute to elevated CVD risk in PWH. This study utilized peripheral blood mononuclear cells (PBMCs) from 25 PWH and 25 HIV-negative controls, as well as HIV in vitro infections. Transcriptional changes were analyzed using RNAseq and pathway analysis. Our results showed that in vitro HIV infection of macrophages and PBMCs from PWH had increased foam cell formation and expression of the NLRP3 inflammasome components and downstream cytokines (caspase-1, IL-1β, and IL-18), which was reduced with inhibition of NLRP3 activity using MCC950. Transcriptomic analysis revealed an increased expression of multiple genes involved in lipid metabolism, cholesterol storage, coronary microcirculation disorders, ischemic events, and monocyte/macrophage differentiation and function with HIV infection and oxLDL treatment. HIV infection and NLRP3 activation increased foam cell formation and expression of proinflammatory cytokines, providing insights into the mechanisms underlying HIV-associated atherogenesis. This study suggests that HIV itself may contribute to increased CVD risk in PWH. Understanding the involvement of the inflammasome pathway in HIV atherosclerosis can help identify potential therapeutic targets to mitigate cardiovascular risks in PWH.

A Perfect Storm: The Convergence of Aging, Human Immunodeficiency Virus Infection, and Inflammasome Dysregulation

“…Moreover, HIV infection in macrophages and peripheral blood mononuclear cells (PBMCs) from PWH showed increased expression levels of NLRP3 inflammasome components and downstream cytokines (including caspase-1, IL-1β, and IL-18), which correlated with various genes linked to cardiovascular disease. This study suggests that HIV infection may exacerbate the risk of cardiovascular disease in PWH by activating NLRP3 [109].…”

Broader Perspective on Atherosclerosis—Selected Risk Factors, Biomarkers, and Therapeutic Approach

“…The NOD-like receptor protein 3 (NLRP3) inflammasome participates in the development of AH [22]. DAMPs (damage-associated molecular patterns), such as LDL, cholesterol crystals, calcium pyrophosphate crystals, uric acid crystals, hyperglycemia, disrupted blood flow, and hypoxia [23], activate the NLRP3 inflammasome, which produces interleukin-1β (IL-1β) via caspase-1-mediated cleavage of pro-IL-1β. The NLRP3 inflammasome is a multimeric cytosolic protein complex composed of pathogen-associated molecular patterns (PAMPs), DAMPs, and neutrophil extracellular traps (NETs) [24], which are proatherosclerotic, cytotoxic, nucleus-derived, and net-like chromatin structures released extracellularly.…”