We have shown that plasma levels of IL-6 are perhaps the most robust predictors of morbidity and mortality in treated HIV-1 infection. The overall objective of this interventional study is to establish the position of heightened IL-6 exposure on the pathways of pathogenesis and morbidity in treated HIV-1 infected persons with immune failure. We propose 3 aims: I. To examine the effects of IL-6 inhibition on the pathogenesis of immune failure and inflammation in treated HIV infection. Our preliminary data have led us to a novel model of HIV immunopathogenesis where the damaged gut is both the source of high levels of IL-6 and where local and systemic exposure to IL-6 sustains the gut mucosal barrier breach and impairs immune restoration even in the presence of antiviral therapy. This is caused by IL-6 mediated inhibition of the IL-7 receptor ? chain - CD127 and IL-6-mediated activation of central memory CD4 T cell cycling and death. We hypothesize that administration of the IL-6 receptor antagonist tocilizumab will decrease the pathologic central memory CD4 T cell cycling and will also restore systemic and gut T cell responses to the homeostatic cytokine IL-7. In the gut and systemically, we will examine the restoration of immune cells, their expression of CD127 and the pro- survival bcl-2 and the gut homing molecule ?4?7 that IL-7 induces, the ability of gut cells to express the gut protective molecules IL-22, IL-17 and the effects of this intervention on local and systemic indices of gut mucosal barrier integrity. II. To examine the effect of systemic IL-6 inhibition on indices of cardiovasculr disease (CVD) risk in treated HIV-1 infection. Increased IL-6 levels have been associated with CVD risk in HIV-1 infection and in the general population and genetic studies also demonstrate a role for IL-6 in CVD risk. During IL-6 receptor blockade, we will monitor blood vessel function, levels of insulin resistance, inflammatory lipids and levels of inflammatory and patrolling monocytes that express the clot forming tissue factor. We will relate them to the effects of IL-6 inhibition on targeted inflammatory markers to be studied in Sp Aim 1 and to the activation pathways that comprise the transcriptomic and metabolomic approaches in Sp Aim 3. III. To examine the effects of systemic IL-6 inhibition on the inflammatory transcriptome and plasma metabolomes in treated HIV-1 infection. Our detailed transcriptional analysis of circulating white blood cells in immune failure patients has found a proinflammatory signature reflective of increased IL-6 exposure and also a strong type 1 interferon signature. At the same time the plasma metabolome in immune failure is consistently distinguishable from those of immune successes and healthy controls with profound perturbations in lipid metabolism with the greatest abnormalities seen in subjects with the highest plasma IL-6 levels. We will examine the effects of IL-6 receptor blockade on the peripheral blood leukocyte transcriptome and plasma metabolome and relate these to functional assays of immune pathogenesis and cardiovascular risk.
This proposal will identify the causal role of a human protein called IL-6 in the course of HIV disease. We suspect that increased levels of IL-6 are driving the failure of the immune system and heart complications in HIV infection even in persons who are treated with antiviral drugs. By blocking IL-6 using a drug called tocilizumab, we will try to correct immune failure and decrease risks of heart disease.
|Shive, Carey L; Clagett, Brian; McCausland, Marie R et al. (2016) Inflammation Perturbs the IL-7 Axis, Promoting Senescence and Exhaustion that Broadly Characterize Immune Failure in Treated HIV Infection. J Acquir Immune Defic Syndr 71:483-92|
|Younes, Souheil-Antoine; Freeman, Michael L; Mudd, Joseph C et al. (2016) IL-15 promotes activation and expansion of CD8+ T cells in HIV-1 infection. J Clin Invest 126:2745-56|
|Shive, Carey L; Jiang, Wei; Anthony, Donald D et al. (2015) Soluble CD14 is a nonspecific marker of monocyte activation. AIDS 29:1263-5|
|Longenecker, Chris T; Triant, Virginia A (2014) Initiation of antiretroviral therapy at high CD4 cell counts: does it reduce the risk of cardiovascular disease? Curr Opin HIV AIDS 9:54-62|