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

项目总结 尽管现代抗逆转录病毒疗法(ART)，艾滋病毒携带者(PLWH)约有50% 增加患心血管疾病的风险。虽然持续的全身炎症似乎可以预测这种风险， 在接受治疗的艾滋病毒感染中，降低炎症和心血管风险的最佳策略仍未确定。 这一提议的首要假设是，无症状巨细胞病毒(CMV)复制是一种 艾滋病病毒感染治疗中心血管风险的重要介体。这一假设得到了以下事实的支持： 巨细胞病毒在血管内皮细胞中复制并在免疫受损的动脉粥样硬化中发挥作用 固体器官移植的接受者。此外，超过90%的PLWH有无症状的CMV合并感染，CMV 经治疗的PLWH患者的脱落水平高于普通人群，CMV的替代标志是 与血管疾病和心肌梗死风险相关的治疗艾滋病毒和治疗无症状巨细胞病毒 早期试验中的复制减少了最具预测性的炎症途径(即sTNFR2) 接受治疗的艾滋病毒中的血管疾病。然而，还没有研究评估是否治疗无症状的CMV复制 在治疗中，PLWH减少了血管炎症和内皮功能障碍的标志物。我们的建议 通过利用一项单独资助的安慰剂对照临床试验来解决这些问题，该试验由 新的CMV终止酶抑制剂letermovir在180ART抑制的ACTG中的PLWH(A5383)。目标1将 用FDG-PET/CT评估48周来特莫韦是否能减轻患者的血管炎症 92名参与者的子集。AIM 2将评估来特莫韦是否降低了血管内皮细胞的血浆标志物 功能障碍和AIM 3将描述雷特莫夫治疗后改变的血浆蛋白质组特征 使用一种改进的适体分析，并将这些变化与血管炎症的同时变化联系起来。 这些研究还得益于强大的MPI团队，他们拥有互补的专业知识和悠久的 合作伙伴包括Hunt博士(艾滋病毒免疫致病机制，临床试验)、Tawakol博士(心脏病学，FDG-PET/CT 成像)和Hsue(艾滋病毒心脏病学，临床试验)；一个与蛋白质组学和生物信息学联合的团队 专业知识(Ganz和Olshen博士)；以及世界上最大的艾滋病毒治疗临床试验网络(ACTG)。 总的来说，这些研究将首次测试经过治疗的艾滋病毒感染--更广泛地说，在人类中--一种 血管疾病中无症状巨细胞病毒复制的潜在原因作用 设计临床试验。如果成功，这项研究可能有助于推动莱特莫韦未来的3期试验，以减少 在接受治疗的艾滋病毒感染的其他并发症中，心血管事件。

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.