Interventions to Reduce Hypercoagulability in Old SIV-Infected NHPs

University Of Pittsburgh At Pittsburgh, Pittsburgh PA

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Abstract

? DESCRIPTION (provided by applicant): A prothrombotic status is characteristic to HIV infection, and is associated with cardiovascular (CV) events and death. The consequences of HIV-related hypercoagulability may be even more severe in elderly, which are disproportionally affected by a prothrombotic status even in the absence of HIV infection. We reported similar coagulation abnormalities in nonhuman primate (NHP) models of AIDS in which increases of D-Dimer (DD) and thrombin-antithrombin complex (TAT) strongly predict disease progression and death. We also showed that, similar to humans, NHPs experience age-related increases of coagulation markers. A strong connection between coagulation and immune activation/inflammation (IA/INFL) markers exists in HIV- infected patients and SIV-infected NHPs. INFL induces expression of tissue factor (TF), a major activator of coagulation. In turn, coagulation factors enhance inflammatory signals via protease-activator receptors, maintaining a coagulation/INFL vicious cycle. Coagulation triggers fibrosis, which impedes CD4+ T cell restoration and may be a reason for ART failure. These observations, together with the finding that DD shows a strong independent risk for mortality in both HIV-infected patients and SIV-infected rhesus macaques (RMs), suggest that coagulation may play a central role in HIV pathogenesis and should be therapeutically targeted. We hypothesize that interventions aimed at limiting hypercoagulation in elderly HIV-infected patients will improve their clinical status an response to ART. We will therefore administer anticoagulants in young vs. older SIVmac-infected RMs with or without ART and assess the impact of these interventions on coagulation status, IA/INFL, fibrosis, CD4+ T cell restoration, CV comorbidities and death. We will use new and FDA- approved anticoagulants specifically targeting the extrinsic, intrinsic and common coagulation pathways. By comparing and contrasting the results of these approaches, we will gain insight into the mechanisms of SIV- and age-related hypercoagulability, independent of factors that usually confound human studies. Such in vivo mechanistic experiments cannot be performed in HIV-infected patients, particularly in older ones, due to the unknown risk of hemorrhages and death. With >50% of the US HIV-infected patients anticipated to be >50 years of age by 2015, the risk of noninfectious complications will be significantly higher and could become the main challenge for the management of chronic HIV infection. As such, our highly innovative, translational experiments address major gaps in our current knowledge of HIV pathogenesis in elderly. By improving the response to ART and preventing CV disease, a major cause of death in ART-treated patients, this research may have a major impact for the clinical management and survival of elderly HIV-infected patients.