Inflammation, Immune Activation, and CVD Risk in Individuals With HIV Infection

Abstract

ANTIRETROVIRAL THERAPY (ART) PROLONGS LIFE, BUT individuals infected with human immunodeficiency virus (HIV) have a shorter life span than their uninfected counterparts and a greater than expected risk of cardiovascular disease (CVD). Part of the increased CVD risk associated with HIV infection can be attributed to an increased burden of traditional risk factors such as cigarette smoking, as well as the effects of ART on lipids, insulin resistance, and body composition. However, increasing evidence suggests that chronic inflammation and immune activation may play key roles in HIV-associated CVD. In individuals without HIV infection, markers of inflammation such as high-sensitivity C-reactive protein (CRP) and interleukin-6 predict CVD events and mortality. Similar although less robust findings have been described in individuals infected with HIV. In an observational study of 70 357 patients from Partners HealthCare, increased CRP levels and presence of HIV were independently associated with risk of acute myocardial infarction. Compared with patients who had normal CRP levels and without HIV infection, the odds ratio for acute myocardial infarction was greater than 4-fold higher among patients with HIV and increased CRP levels. In the Strategies for Management of Antiretroviral Therapy (SMART) study, interruption of ART was associated with greater mortality and CVD events compared with continuous ART, and higher levels of interleukin-6 and D-dimers were associated with all-cause mortality, suggesting that improvements in mortality in the setting of continuous ART may be mediated by a reduction in inflammation. Furthermore, among treatment-naive individuals infected with HIV, initiation of ART improved endothelial function within 4 weeks of treatment despite worsening lipids and the degree of improvement was associated with lower HIV RNA-1 levels. Taken together, these findings suggest that immediately after initiation, ART reduces CVD risk by decreasing inflammation and viral replication, despite having adverse effects on traditional CVD risk factors. However, individuals receiving treatment who have suppression of HIV replication have higher levels of inflammatory markers than uninfected individuals and persistent inflammation while taking ART appears to increase long-term CVD risk. The factors that contribute to ongoing inflammation and immune activation in the setting of chronic, treated HIV infection are incompletely understood and likely are different than in individuals without HIV in whom inflammation is driven, in large part, by visceral adiposity and its associated metabolic abnormalities. Depletion of CD4 cells in gut mucosal lymphoid tissue occurs early in HIV infection and may contribute to ongoing microbial translocation. This process is not completely reversed with ART, even when HIV replication appears to be suppressed. Increased levels of lipopolysaccharide and soluble CD14 (sCD14) persist in some individuals with treated HIV infection, suggesting that intestinal microbial translocation may contribute to persistent immune activation. Furthermore, increased levels of sCD14 are associated with increased all-cause mortality and HIV disease progression, as well as more rapid progression of carotid atherosclerosis. Other putative drivers of cellular activation and associated cytokine secretion include indirect effects of HIV gene products, direct infection of macrophages by HIV, and antigenic stimulation by latent viruses that are common in patients with HIV. Immunological abnormalities that are affected directly by HIV infection such as current and nadir CD4 cell count have been independently associated with CVD risk, as have markers of immune activation and senescence. In this issue of JAMA, Subramanian et al describe for the first time imaging of arterial wall inflammation using fluorine-2-deoxy-D-glucose positron emission tomography (FFDG-PET) in individuals with HIV. In a small crosssectional study, the authors demonstrated that individuals with HIV but without known coronary artery disease have higher aortic uptake of FDG (expressed as the target-tobackground ratio [TBR]) than risk factor–matched individuals without HIV, and have a level of aortic TBR similar to that of individuals without HIV with coronary artery disease. Patients with HIV infection had higher aortic TBR than controls even after adjusting for traditional CVD risk fac-