HIV Infection Drives Foam Cell Formation via NLRP3 Inflammasome Activation

Area of Science:

• Immunology
• Cardiovascular Science
• Infectious Disease

Background:

• Persistent immune activation is a known risk factor for cardiovascular disease (CVD) in people with HIV (PWH) receiving antiretroviral therapy (ART).
• The NLRP3 inflammasome, an intracellular protein complex, is implicated in inflammatory processes and may play a role in the heightened CVD risk observed in PWH.

Purpose of the Study:

• To investigate the role of the NLRP3 inflammasome in HIV-associated cardiovascular disease.
• To explore the mechanisms by which HIV infection and NLRP3 activation contribute to atherogenesis in PWH.

Main Methods:

• Analysis of peripheral blood mononuclear cells (PBMCs) from PWH and HIV-negative controls.
• In vitro HIV infection models of macrophages and PBMCs.
• RNA sequencing (RNAseq) and pathway analysis to assess transcriptional changes.
• Inhibition of NLRP3 inflammasome activity using MCC950.

Main Results:

• HIV infection and oxLDL treatment increased foam cell formation and expression of NLRP3 inflammasome components (caspase-1, IL-1β, IL-18) in macrophages and PBMCs.
• Transcriptomic analysis revealed altered expression of genes related to lipid metabolism, cholesterol storage, and monocyte/macrophage function.
• Inhibition of NLRP3 activity with MCC950 reduced inflammasome activation and foam cell formation.
• HIV infection and NLRP3 activation were linked to increased pro-inflammatory cytokine expression.

Conclusions:

• HIV infection itself, through NLRP3 inflammasome activation, contributes to atherogenesis and increased CVD risk in PWH.
• The NLRP3 inflammasome pathway is a key player in the mechanisms underlying HIV-associated cardiovascular complications.
• Targeting the NLRP3 inflammasome may represent a potential therapeutic strategy to mitigate CVD risk in PWH.