Impact of Treating Asymptomatic CMV Replication on Cardiovascular Risk in Treated HIV Infection

项目摘要 尽管有现代抗逆转录病毒疗法（ART），艾滋病毒感染者（PLWH）仍有大约50%的人感染了艾滋病毒。 增加心血管疾病的风险。虽然持续的全身炎症似乎可以预测这种风险， 在治疗HIV感染中减少炎症和心血管风险的最佳策略仍不明确。 该建议的首要假设是，无症状巨细胞病毒（CMV）复制是一种 心血管风险的重要介质治疗艾滋病毒感染。这一假设得到以下事实的支持： CMV在血管内皮中复制，似乎在免疫功能低下患者的动脉粥样硬化中起作用。 实体器官移植接受者此外，超过90%的PLWH有无症状的CMV合并感染，CMV 治疗的PLWH中的脱落水平高于一般人群，CMV的替代标志物是 与接受治疗的HIV患者的血管疾病和心肌梗死风险相关， 早期试验中的复制减少了炎症途径（即，sTNFR 2）最强预测 血管疾病的治疗艾滋病毒。然而，没有研究评估治疗无症状CMV复制是否 在治疗PLWH减少血管炎症和内皮功能障碍的标志物。我们的建议 通过利用由Hunt博士领导的单独资助的安慰剂对照临床试验来解决这些问题。 新型CMV末端酶抑制剂莱特莫韦治疗ACTG中180例ART抑制的PLWH（A5383）。目标1将 确定48周的莱特莫韦是否减少了血管炎症，如通过FDG-PET/CT评估的， 共有92名参与者。目的2将评估莱特莫韦是否减少内皮细胞的血浆标志物， 功能障碍和目标3将表征莱特莫韦治疗改变的血浆蛋白质组特征 并将这些变化与血管炎症的并发变化联系起来。 这些研究还得益于强大的MPI团队，他们具有互补的专业知识和悠久的历史， Hunt博士（HIV免疫发病机制，临床试验）、Tawakol博士（心脏病学，FDG-PET/CT 成像）和Hsue（HIV心脏病学，临床试验）;一个与蛋白质组学和生物信息学合作的团队 Ganz博士和Olshen博士）;以及世界上最大的HIV治疗临床试验网络（ACTG）。 总的来说，这些研究将首次测试治疗的艾滋病毒感染-更广泛地在人类- 无症状CMV复制在血管疾病中的潜在因果作用， 设计的临床试验。如果成功，这项研究可能有助于激励未来的莱特莫韦3期试验，以减少 心血管事件和其他并发症。

PROJECT SUMMARY Despite modern antiretroviral therapy (ART), people living with HIV (PLWH) have an approximately 50% increased risk of cardiovascular disease. While persistent systemic inflammation appears to predict this risk, the optimal strategies to reduce inflammation and cardiovascular risk in treated HIV infection remain undefined. The overarching hypothesis of this proposal is that asymptomatic cytomegalovirus (CMV) replication is an important mediator of cardiovascular risk in treated HIV infection. This hypothesis is supported by the fact that CMV replicates in vascular endothelium and appears to play a role in atherosclerosis in immunocompromised solid-organ transplant recipients. Furthermore, over 90% of PLWH have asymptomatic CMV co-infection, CMV shedding levels are higher in treated PLWH than in the general population, surrogate markers of CMV are associated with vascular disease and myocardial infarction risk in treated HIV, and treating asymptomatic CMV replication in an earlier trial reduced the inflammatory pathways (i.e., sTNFR2) that most strongly predict vascular disease in treated HIV. Yet, no study has assessed whether treating asymptomatic CMV replication in treated PLWH reduces vascular inflammation and markers of endothelial dysfunction. Our proposal addresses these issues by leveraging a separately funded placebo-controlled clinical trial led by Dr. Hunt of the novel CMV terminase inhibitor letermovir in 180 ART-suppressed PLWH in the ACTG (A5383). Aim 1 will determine whether 48 weeks of letermovir reduces vascular inflammation as assessed by FDG-PET/CT in a subset of 92 participants. Aim 2 will assess whether letermovir reduces plasma markers of endothelial dysfunction and Aim 3 will characterize the plasma proteomic signatures that are altered by letermovir therapy using a modified aptamer assay and relate these changes to concurrent changes in vascular inflammation. These studies also benefit from a strong MPI team with complementary expertise and a long history of collaboration including Drs. Hunt (HIV immunopathogenesis, clinical trials), Tawakol (cardiology, FDG-PET/CT imaging), and Hsue (HIV cardiology, clinical trials); a team of co-Is with proteomics and bioinformatics expertise (Drs. Ganz and Olshen); and the largest HIV therapeutics clinical trials network in the world (ACTG). Collectively, these studies will test for the first time treated HIV infection – and more broadly in humans - a potential causal role of asymptomatic CMV replication in vascular disease in the context of a rigorously designed clinical trial. If successful, this study could help motivate a future Phase 3 trial of letermovir to reduce cardiovascular events among other complications in treated HIV infection.