HIV-1-Associated Atherosclerosis: Unraveling the Missing Link

Abstract

Cardiovascular disease, including atherosclerosis and atherosclerosis-associated complications, is an increasing cause of morbidity and mortality in human immunodeficiency virus (HIV) patients in the post-antiretroviral therapy era. HIV alone accelerates atherosclerosis. Antiretroviral therapy; HIV-associated comorbidities, such as dyslipidemia, drug abuse, and opportunistic infections; and lifestyle are risk factors for HIV-associated atherosclerosis. However, our current understanding of HIV-associated atherogenesis is very limited and has largely been obtained from clinical observation. There is a pressing need to experimentally unravel the missing link between HIV and atherosclerosis. Understanding these mechanisms will help to better develop and design novel therapeutic interventions for the treatment of HIV-associated cardiovascular disease. HIV mainly infects T cells and macrophages resulting in the induction of oxidative and endoplasmic reticulum stress, the formation of the inflammasome, and the dysregulation of autophagy. These mechanisms may contribute to HIV-associated atherogenesis. In this review, we will summarize our current understanding and propose potential mechanisms of HIV-associated atherosclerosis.

Keywords: Tg26 transgenic mice; caspase-1; immune activation; inflammasome; inflammation; macrophage.

Central Illustration. Cellular and Molecular Mechanisms of HIV Atherogenesis

(A) Cellular players in the initiation, progression, and plaque rupture of HIV-associated atherosclerosis. 1) HIV enhances the inflammatory environment, causing an increase in atherogenic monocytes, HLA-DR⁺CD38⁺ T cells, cytokines, and chemokines. 2) The increase in atherogenic monocytes and chemokines increases monocyte migration into the vasculature. 3) HIV increases foam cell formation. 4) HIV decreases smooth muscle cell proliferation and increases endothelial and foam cell apoptosis, making the plaque more vulnerable to rupture. (B) Molecular mechanisms in an HIV-infected macrophage contributing to atherogenesis: 1) increased OS; 2) increased ER stress; 3) increased inflammasome activation and cytokine production; 4) decreased autophagy. These molecular mechanisms amplify each other and are further complicated by ART and HIV risk factors and comorbidities. ART = antiretroviral therapy; CRP = C-reactive protein; ER = endoplasmic reticulum; HCV = hepatitis C virus; HIV = human immunodeficiency virus; IL = interleukin; LDL = low-density lipoprotein; NADPH = nicotinamide adenine dinucleotide phosphate; OS = oxidative stress; oxLDL= oxidized low-density lipoprotein; PRR = pathogen recognition receptor; ROS = reactive oxygen species; TNF = tumor necrosis factor; VCAM-1 = vascular cell adhesion molecule-1.