Rosuvastatin treatment reduces markers of monocyte activation in HIV infected subjects on antiretroviral therapy

Inflammation and immune activation may contribute to the progression of cardiovascular disease (CVD) in the general population [1, 2]. Patients infected with the human immunodeficiency virus (HIV) appear to have a greater risk for CVD than uninfected controls [3–6], and within HIV-infected subjects, markers of inflammation, immune activation, and coagulation are associated with mortality, HIV disease progression, vascular disease, and diabetes [7–11]. The drivers of increased inflammation and cardiovascular risk in HIV disease remain unclear, but have been attributed to coinfections with agents such as cytomegalovirus [12], to persistence of HIV replication in sanctuary sites [13], by exposure to bioactive lipids [14–16], to homeostatic cytokines [17], and to microbial elements translocated through a damaged gut [18]. Activated monocytes may contribute to inflammation and cardiovascular disease [19]. Three monocyte subsets can be identified based on CD14 and CD16 expression [20–23]. Traditional (CD14+CD16−) monocytes engulf and present antigen. Patrolling (CD14DimCD16+) monocytes home to the vascular endothelium and recognize viral products; inflammatory (CD14+CD16+) monocytes produce high levels of inflammatory cytokines in response to bacterial products [22]. Proportions of monocytes from HIV-infected donors, and uninfected donors who have recently had an acute coronary event, are enriched for patrolling and inflammatory monocytes, and these cells have a procoagulant phenotype [24]. Soluble CD14 (sCD14), a marker of monocyte activation, is an independent predictor of mortality in HIV-infected subjects [9] and has been linked to faster vascular disease progression, as measured by carotid intima-media thickness [25]. Similarly, the macrophage activation marker soluble CD163 (sCD163) is associated with noncalcified plaques in the coronary arteries [26] and with arterial inflammation in HIV-infected subjects [27]. These markers provide a link between myeloid cell activation and cardiovascular risk in HIV disease. Identifying successful therapies that would reduce chronic immune activation in treated HIV disease is an ongoing research priority. Statins, or 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, have anti-inflammatory effects beyond those related to cholesterol lowering [28, 29]. Several statin studies have been performed in HIV-infected subjects, but most were aimed at the effects of statins on lipid levels and on HIV viremia [30–34]. Recently, administration of high-dose atorvastatin (80 mg) modestly reduced the proportion of HLA-DR–expressing CD8+ T cells in HIV-infected subjects who were not receiving antiretroviral therapy (ART) [35]. In our current study, the Stopping Atherosclerosis and Treating Unhealthy Bone With Rosuvastatin in HIV (SATURN-HIV) trial, HIV-infected subjects who were undergoing successful ART and had normal low-density lipoprotein (LDL) cholesterol levels, but elevated levels of inflammation and immune activation, were randomized to receive rosuvastatin (10 mg daily) or placebo. We present the results of a prespecified secondary analysis aimed at assessing the effects of statin administration on markers of immune activation and inflammation, including plasma levels of monocyte/macrophage activation markers (sCD14 and sCD163), and proportions of activated T cells and monocytes.