Chronic infection by HIV increases the risk of cardiovascular disease (CVD) despite effective antiretroviral therapy (ART). HIV-1 infected subjects. Participants were 45 years or older on virologically suppressive ART and at risk for CVD. This group was compared to 14 HIV-negative subjects matched for age and gender with similar CVD risk. We simultaneously detected intracellular expression of IL-1β IL-6 IL-8 and TNF in blood monocytes in the basal state and after stimulation by triggers commonly found in the blood of treated chronically HIV-infected subjects: lipopolysaccharide (LPS) and oxidized low-density lipoprotein (oxLDL). In the absence Rabbit polyclonal to A2LD1. of stimulation monocytes from treated HIV-infected subjects displayed a high frequency of cells producing IL-1β (median 19.5%) AZD2281 compared to low levels in HIV-uninfected persons (0.9% p<0.0001). IL-8 which is induced by IL-1β was also highly expressed in the HIV-infected group in the absence of stimulation 43.7% compared to 1.9% in HIV-uninfected subjects p<0.0001. Strikingly high basal expression of IL-1β by monocytes predicted high IL-6 levels in the plasma and high monocyte IL-6 responses in HIV-infected subjects. Hyper-inflammatory IL-1β enriched monocytes may be a major source of IL-6 production and systemic inflammation in HIV-infected adults and may contribute to the risk for all-cause mortality and cardiovascular disease in treated HIV infection. Introduction High blood plasma IL-6 is a biomarker of cardiovascular disease (CVD) risk in adults [1] and is associated with increased overall mortality in adults with HIV-1 infection (HIV+) [2]. HIV+ adults are at elevated risk for developing CVD [3 4 however it remains unclear how HIV infection contributes to this risk and what mechanisms may be involved. Determination of routes by which IL-6 comes to be expressed to high levels in the blood during AZD2281 HIV infection namely the source of its production and triggers may shed light on HIV-driven processes that increase risk for all-cause mortality and CVD and in turn reveal clues in the search for new markers of CVD risk in HIV. Indeed an effective biomarker of CVD risk that is specific to the HIV+ population has not yet emerged [5]. IL-6 is one candidate biomarker among several. Studies based on the SMART (Strategies for Management of Anti-Retroviral Therapy) trial indicate that HIV-1 infected patients who initiate and remain on anti-retroviral therapy (ART) show sustained reductions in levels of inflammatory agents such as IL-6 C-Reactive Protein (CRP) and D-Dimer as well as improvements in high-density lipoprotein (HDL) and low-density lipoprotein (LDL) levels and their respective transport proteins ApoA1 and ApoB [5]. However the degree of improvement of HDL-particle AZD2281 (HDL-p) and ApoA1 levels was lower in those with high baseline CRP and IL-6 indicating a relationship between high chronic immune inflammation and an impaired ability to resolve dyslipidemia in chronic HIV infection. The authors suggest that the beneficial effects of ART on dyslipidemias may be driven by reductions in immune inflammation. Understanding the mechanisms behind elevated chronic immune inflammation in HIV and in particular its relation to IL-6 levels in the blood may inform strategies to target immune inflammation and persistent dyslipidemias that contribute to CVD risk and other sources of morbidity [6] and mortality in chronic HIV infection. Recently studies of HIV chronic inflammation have increasingly focused on blood monocytes a population of cells AZD2281 with inflammatory properties known to be involved in promotion of atherosclerosis [7 8 Monocytes are circulating highly secretory cells that respond to a wide range of stimuli including microbial products and oxidized lipoproteins. These cells represent an important source of cytokines and chemokines and may be major contributors to systemic immune inflammation in HIV disease. Monocytes produce IL-1β a pleiotropic cytokine having multiple and diverse inflammatory properties [9]. Indeed IL-1β is considered the gatekeeper of inflammation [10] and triggers many secondary responses including IL-6 production in monocytes [11]..