Role of caspase-1 activation in HIV-1 associated atherogenesis

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Project summary/Abstract: Atherosclerosis-associated cardiovascular disease (CVD) is currently one of the leading causes of mortality among people living with HIV (PLWH) on effective antiretroviral therapy (ART). Our current understanding of the pathogenesis of HIV-associated atherosclerosis is limited and largely obtained from clinical observations. The distinct pathologic features of HIV-induced atherosclerosis are noncalcified inflammatory plaques that are more vulnerable to rupture. In patients on ART treatment, HIV infection not only activates immune cells, such as macrophages (MC), but also activates an array of molecular pathways, such the inflammasome pathway, including caspase-1 (casp-1) activation. However, the exact cellular and molecular mechanisms underlying HIV-associated atherogenesis have not been extensively investigated. Understanding these mechanisms will help to better develop and design novel therapeutic interventions for the treatment/prevention of HIV-associated CVD. To achieve this unmet goal, we have formed a multidisciplinary team consisting of multiple PIs Dr. Qin (innate immunity and CVD expert) and Dr. Burdo (expert in HIV-1 CVD and macrophage (Mϕ) biology), and Co-I Dr. Gordon (expert in HIV-1 infection). Through this joint effort, we have utilized HIV-transgenic mice (Tg26 on a B6 background) carrying a 7.4-kb proviral HIV DNA construct carrying a deletion, encompassing most of the gag and pol genes, to render it noninfectious. Tg26 mice mimic chronic HIV patients on ART in which there is no viral replication, but viral proteins are still produced. In order to introduce Tg26 to an atherogenic background, we crossed this line with Apolipoprotein E (ApoE-/-) mice, a common mouse strain used for studying atherogenesis for the last 25 years to generate Tg26/ApoE-/- mice. Our preliminary results show that 1) Tg26/ApoE-/- developed an accelerated atherogenesis with normal renal function, 2) Tg26/ApoE-/- had significantly higher casp-1 activation in peripheral blood mononuclear cells (PBMC) and plaques than ApoE-/-, 3) The HIV-1 transgene in Tg26/ApoE-/- fostered MC to form the foam cells, a hallmark of atherogenesis, and 4) Casp-1 is activated on MC in the plaques of HIV-1-infected patients, and 5) serum IL-1 and IL-18 are elevated in Tg26 and IL-18 is elevated in HIV+ patients and correlates with coronary plaque. Therefore, we hypothesize that chronic HIV infection induces MC activation via casp-1 pathway, contributing to HIV-associated atherogenesis. To test this hypothesis, we propose to investigate the pathogenesis of HIV-1-associated atherosclerosis by using animal models and available HIV specimens. We will use several novel models and approaches including our newly established HIV-1 Tg-26 transgenic mice maintained under hyperlipidemia conditions as well as standard approaches including our established in vitro model systems for foam cell formation. The proposed studies will provide important insights into our understanding of the role of HIV-1 infection and immune activation in atherosclerosis.