Anti-cytomegalovirus Immune Responses in Atherosclerotic Cardiovascular Disease in Persons Living with HIV

HIV 感染者动脉粥样硬化性心血管疾病的抗巨细胞病毒免疫反应

• 批准号: 10326646
• 负责人: Celestine N Wanjalla
• 金额: $ 18.52万
• 依托单位: VANDERBILT UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-25 至 2026-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10326646
• 关键词: ADGR1 gene; AIDS/HIV problem; Acquired Immunodeficiency Syndrome; Address; Adult; Animal Model; Antibodies; Antibody Response; Aorta; Arterial Fatty Streak; Atherosclerosis; Award; Biology; Blood; Blood Vessels; CD4 Positive T Lymphocytes; Cardiac; Cardiovascular Diseases; Cardiovascular system; Cause of Death; Cell Line; Cells; Cellular Immunity; Chimera organism; Chronic; Clinical Research; Collaborations; Communicable Diseases; Coronary artery; Cytomegalovirus; Data; Development; Development Plans; Disease Pathway; Endothelium; Epidemiology; Epitopes; Event; Foundations; Funding; HIV; HIV Seronegativity; Home; Human; Image; Immune; Immune response; Immunology; Implant; Individual; Infiltration; Inflammation; Infrastructure; Intervention Trial; Knowledge; Label; Leadership; Ligands; Linear Regressions; Link; Measures; Mentored Patient-Oriented Research Career Development Award; Mentors; Metabolic Diseases; Mission; Modeling; Morbidity - disease rate; Mus; National Heart, Lung, and Blood Institute; Pathogenesis; Peripheral; Peripheral Blood Mononuclear Cell; Persons; Phenotype; Physicians; Population; Publishing; Regression Analysis; Research; Research Priority; Resources; Risk Factors; Role; SECTM1 gene; Science; Scientist; Structure of thyroid parafollicular cell; Subgroup; Surface; T memory cell; T-Cell Receptor; T-Lymphocyte; T-cell receptor repertoire; Tennessee; Testing; Tissues; Training; Translational Research; United States National Institutes of Health; Virus; Work; X-Ray Computed Tomography; antiretroviral therapy; cardiovascular disorder risk; cardiovascular risk factor; career development; chemokine receptor; co-infection; cohort; health difference; high risk; immunomodulatory strategy; intravenous administration; microbial; mortality; mortality risk; mouse model; novel; peripheral blood; recruit; responsible research conduct; seropositive; skills

Project Summary Persons with HIV (PWH) have an approximate 2-fold higher risk of cardiovascular disease (CVD) compared to HIV-negative individuals, which is not explained by traditional risk factors and persists despite effective antiretroviral therapy. Some evidence suggests that cytomegalovirus (CMV), an almost universal co-infection in many subgroups of PWH, may be linked to increased CVD risk. However, CMV seropositivity alone (i.e., the presence of anti-CMV antibodies) has been insufficient as a predictor of CVD, potentially due to the greater importance of cellular immunity in the CMV-CVD pathway. Cardiovascular events are the leading cause of death in PWH and although CMV is thought to be important, its specific contribution to CVD in PWH is unclear. Current knowledge on the contribution of CMV to CVD is limited in several ways: 1) Few human studies have assessed peripheral blood circulating anti-CMV T cells and prevalent atherosclerosis. 2) There is a paucity of data on whether CMV-specific T cells are present within human atherosclerotic plaque. 3) At present there is not a reliable animal model to investigate the infiltration of virus-specific T cells into plaque. We have shown that CD4+ T cells co-expressing the surface markers CX3CR1, GPR56 and CD57 (i.e. `C-G-C') are largely CMV- specific. We also showed that C-G-C+ CD4+ T cells are increased in the blood of PWH with metabolic disease and subclinical atherosclerosis. As the chemokine receptor CX3CR1 is highly expressed on CMV-specific T cells and traffics cells to activated endothelium, we hypothesize that inflated anti-CMV C-G-C+ CD4+ T cells recruited to inflamed endothelium via CX3CR1 are a major driver of subclinical atherosclerosis in PWH. I am a physician scientist skilled in immunology and microbial pathogenesis with training in infectious diseases. My tailored career development plan will advance my skills through experiential, didactic and professional training in: (1) tissue immunology; (2) atherosclerosis-pathogenesis; (3) clinical and translational research; (4) human-mouse chimera models; and (5) responsible conduct of research. With a transdisciplinary mentoring panel with expertise in HIV clinical research, epidemiology, single cell immunology, CVD, and atherosclerosis, I will accomplish the following aims. In Aim 1, we will test the hypothesis that peripheral C-G-C+ CD4+ T cells are CMV-specific and associated with subclinical atherosclerosis in PWH. In Aim 2, we will test the hypothesis that plaque-infiltrating C-G-C+ CD4+ T cells are CMV-specific. In Aim 3, we will use a mouse model to test the hypothesis that recruitment of circulating CMV-specific C-G-C+ CD4+ T cells to inflamed atheroma is CX3CR1-dependent. Completion of these specific aims will increase our understanding of whether CMV has an important role in CVD in PWH. With the completion of my career development plan, I will gain expertise in clinical and translational research, vascular biology, and cutting-edge immunology. The completion of this K23 award will allow me to transition to become an independent physician scientist in the cardio-immunology space with concentration on virus-specific immune responses.

项目摘要 艾滋病毒感染者（PWH）患心血管疾病（CVD）的风险约为 艾滋病毒阴性个体，这不能用传统的风险因素来解释，尽管有效，但仍然存在 抗逆转录病毒疗法一些证据表明，巨细胞病毒（CMV），一种几乎普遍的合并感染， PWH的许多亚组可能与CVD风险增加有关。然而，单独的CMV血清阳性（即，的 抗CMV抗体的存在）不足以作为CVD的预测因子，可能是由于 细胞免疫在CMV-CVD途径中的重要性。心血管事件是导致死亡的主要原因 虽然CMV被认为是重要的，但其对PWH中CVD的具体贡献尚不清楚。电流 关于CMV对CVD的贡献的知识在几个方面是有限的：1）很少有人类研究评估 外周血循环抗CMV T细胞和普遍的动脉粥样硬化。2)有一个数据匮乏， CMV特异性T细胞是否存在于人动脉粥样硬化斑块内。3)目前没有一个 研究病毒特异性T细胞向斑块浸润的可靠动物模型。我们已经证明 共表达表面标志物CX 3CR 1、GPR 56和CD 57（即“C-G-C”）的CD 4 + T细胞主要是CMV-T细胞。 特定.我们还发现，在PWH合并代谢性疾病的血液中，C-G-C+ CD 4 + T细胞增加 和亚临床动脉粥样硬化。作为趋化因子受体，CX 3CR 1在CMV特异性T细胞上高度表达 并将细胞运输到活化的内皮细胞，我们假设膨胀的抗CMV C-G-C+ CD 4 + T细胞募集了 炎症内皮细胞通过CX 3CR 1是PWH亚临床动脉粥样硬化的主要驱动因素。我是一名医生 在免疫学和微生物致病机理方面有丰富经验的科学家，受过传染病方面的培训。我量身定制的职业生涯 我的发展计划将通过经验、教学和专业培训来提高我的技能：（1）组织 免疫学;（2）动脉粥样硬化-发病机制;（3）临床和转化研究;（4）人鼠嵌合体 （5）负责的研究行为。有一个具有艾滋病毒专门知识的跨学科指导小组 临床研究、流行病学、单细胞免疫学、心血管疾病和动脉粥样硬化，我将完成以下工作 目标。在目的1中，我们将检验外周血C-G-C+ CD 4 + T细胞是CMV特异性的并且与CMV相关的假设。 与PWH中的亚临床动脉粥样硬化相关。在目的2中，我们将检验斑块浸润性C-G-C+ CD 4 + T细胞是CMV特异性的。在目标3中，我们将使用小鼠模型来检验循环细胞的募集 CMV特异性C-G-C+ CD 4 + T细胞对炎性动脉粥样硬化的作用依赖于CX 3CR 1。完成这些具体 目的将增加我们对CMV是否在PWH的CVD中起重要作用的理解。完成后 在我的职业发展计划中，我将获得临床和转化研究、血管生物学和 尖端的免疫学K23奖的完成将使我能够过渡到成为一个独立的 心脏免疫学领域的医生科学家，专注于病毒特异性免疫反应。