HIV infection elevates the risk for cardiovascular disease (CVD) independent of traditional risk factors. Autopsy series document cardiac fibrosis in the HIV+ treatment naive, observations supported by necropsies of simian immunodeficiency virus-infected macaques. Key histologic features include chronic inflammation and endomyocardial fibrosis. The magnitude of overall clinical CVD risk is low, but increases substantially with certain types of antiretroviral therapy (ART). Recent gadolinium enhancement MR imaging documented patchy and diffuse myocardial fibrosis in 76% of 90 HIV+ individuals on ART, while only 13% of control subjects had evidence of any myocardial fibrosis. Clinically, ritonavir (RTV)-boosted protease inhibitor therapies appear linked to greater increases in CVD prevalence. RTV-treated rodents exhibit cardiac dysfunction, dysregulation of the ubiquitin- proteasome system, and cardiac fibrosis. Although hyperlipidemia and hypercoaguable changes complicate dissection of primary etiologic events, cardiac fibrosis in RTV-treated rodents, and elevation in inflammatory markers and preclinical indices of atherosclerosis in RTV treated HIV+ patients, have been documented, independent of RTV-linked lipid alterations. We therefore focus on HIV/ART and its relationship to cardiac fibrosis. We postulate that in the HIV+ but ART naive, fibrosis is a consequence of proinflammatory cytokine linked induction of tissue factor, leading to thrombin generation, platelet activation wit release of transforming growth factor (TGF)1, and Smad and TAK1/MKK3/p38-mediated signaling, resulting in accelerated collagen synthesis. In addition, physiologic facilitators of collagen degradation, such as Beclin1, may be blocked by soluble HIV gene products. In terms of ART, we had shown that RTV inhibits degradation of TRAF6 in the immunoproteasome, augmenting the function of this nuclear signaling adapter molecule for the osteoclast differentiating cytokine RANKL, leading to accelerated bone mineral loss and osteopenia. We now hypothesize that a similar RTV- mediated phenomenon amplifies TRAF6 associated TGF-1 signaling and cardiac fibrosis, and might be targeted through a novel approach: use of carbon monoxide or CO inducers, some already in pilot clinical trials for pulmonary fibrosis. Successful completion of these pilot studies will be facilitated by our ongoing model for platelet TGF1-driven cardiac fibrosis in mice, our long investment in the study of ART-mediated alterations in TRAF6 signaling, and a clinical resource: banked plasma, serum and PBMC samples from 100 HIV+ and 100 HIV- women followed longitudinally for two years, the former either treatment-naive or on RTV-based versus other ART. These data should support proposals to pursue additional translational studies related to HIV/ART and CVD in our lab, as well as suggest possible clinical trials to intervene in HIV-associated CVD.
Overall risk for cardiovascular disease among the HIV+ treatment-naive is low, but this risk increases substantially in individuals on certain types of antiretroviral therapy (ART), particularly ritonavir-boosted protease inhibitors. These disorders are predicted to worsen with aging, and may prove an important obstacle toward reaching a normal lifespan in HIV disease. While multiple mechanisms have been proposed to explain changes in cardiac function linked to HIV/ART, we focus on fibrosis. Our approach, including in vitro and murine models to explore the potential for low levels of clinicall relevant agents to enhance physiologic mediators of inflammation and fibrosis, could eventually open novel therapeutic interventions.