Immune Dysfunction in HIV-Associated Cardiometabolic Disease: Insights, Emerging Perspectives, and Clinical Implications

Although the widespread use of antiretroviral therapy (ART) has significantly increased the lifespan of people living with HIV (PLWH), it has resulted in the emergence of comorbidities unrelated to acquired immunodeficiency syndrome (AIDS), particularly cardiometabolic disease (CMD). The development of CMD in PLWH is driven by the interaction between persistent immune activation and ART-associated metabolic changes, thus contributing to oxidative stress, inflammation, insulin resistance, dyslipidaemia, hypertension, and atherosclerosis. Chronic inflammation further promotes tissue fibrosis through cytokine-mediated pathways, including interleukin-6 (IL-6), tumour necrosis factor alpha (TNF-α), and transforming growth factor beta (TGF-β). This narrative review explores the immunometabolic mechanisms underlying CMD in PLWH on ART, with a core focus on immune cell subset changes, oxidative stress, chronic inflammation, and T-cell exhaustion. The continued presence of immune dysregulation, despite ART adherence and viral suppression, contributes to endothelial dysfunction, metabolic imbalances, and the progression of cardiovascular complications. Furthermore, the prolonged immune activation promotes a pro-inflammatory and pro-oxidative environment that induces vascular injury and CMD. There remains a critical need for longitudinal research in underrepresented populations to better understand the long-term cardiometabolic consequences of HIV infection and ART. The improved characterisation of immunometabolic regulation may support earlier detection of high-risk individuals and inform more specific, targeted strategies to reduce CMD progression in PLWH. Clinically, this approach supports routine cardiometabolic screening, while also considering the effects of HIV-specific inflammation, ART exposure, and immune dysfunction in high-risk individuals.