Inflammation, immune activation, and cardiovascular disease in HIV

Abstract

Cardiovascular disease is one of the leading causes of morbidity and mortality in people living with HIV. Several epidemiological studies have shown an increased risk of myocardial infarction and stroke compared to uninfected controls. Although traditional risk factors contribute to this increased risk of cardiovascular disease, HIV-specific mechanisms likely also play a role. Systemic inflammation has been linked to cardiovascular disease in several populations suffering from chronic inflammation, including people living with HIV. Although antiretroviral therapy reduces immune activation, levels of inflammatory markers remain elevated compared to uninfected controls. The causes of this sustained immune response are likely multifactorial and incompletely understood. In this review, we summarize the evidence describing the relationship between inflammation and cardiovascular disease and discuss potential anti-inflammatory treatment options for cardiometabolic disease in people living with HIV.

Conflict of interest statement

Conflicts of Interest: S.K.G has consulted with Navidea, AstraZeneca, NovoNordisk, Theratechnologies, Bristol Myers Squibb, Merck, and Gilead, and received grant support from Gilead, Amgen, KOWA Pharmaceuticals, Navidea, and Theratechnologies, unrelated to this manuscript. J.L. has consulted with Gilead, unrelated to this manuscript. E.N. declares no competing interests.

Figures

Figure 1

Effects of HIV Viral Proteins on the Development of Atherosclerosis. In vitro studies have shown the following proatherogenic effects of HIV viral proteins: A) Tat and gp120 induces expression of adhesion molecules [179, 180]; B) Nef and gp120 reduce endothelial NO production [181, 182]; C) Nef increases inflammatory cytokine release including IL-6 and TNF-alpha from macrophages [183]; D) Nef promotes MCP-1 secretion from endothelial cells [184]; E) Tat stimulates MCP-1 mediated monocyte transmigration [185]; F) Nef inhibits ABCA1-dependent CEC of macrophages [76]; G) Nef and gp120 may induce endothelial apoptosis, which could promote fibroatheroma rupture/erosion, resulting in formation of an acute thrombus [186, 187]; H) Tat stimulates IL-6 production from peripheral blood monocytes [188]. In vitro studies have also shown potential proatherogenic effects of specific ARTs including increased leukocyte adhesion to endothelial cells with efavirenz [189]; increased platelet reactivity with abacavir [190]; reduced cholesterol efflux from macrophages, decreased endothelial nitric oxide production, and endothelial cytotoxicity with ritonavir [–193]; and CD36-dependent cholesterol accumulation in macrophages with certain protease inhibitors [194]. ABCA1 = ATP-binding cassette transporter-A1, CEC = cholesterol efflux capacity, RCT = reverse cholesterol transport, TF = tissue factor, HDL = high-density lipoprotein, LDL = low-density lipoprotein, oxLDL = oxidized LDL, MCP-1 = monocyte chemoattractant protein-1.

Figure 2

Pathways Involved in the Development of Immune Activation and Atherosclerosis in HIV. Arrows indicate a contributory effect. Terminal lines indicate an inhibitory effect. Dotted Lines indicate a potential yet uncertain relationship. cART = combined antiretroviral therapy, RCT = reverse cholesterol transport, CEC = cholesterol efflux capacity, GI = gastrointestinal, LDL = low-density lipoprotein.