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: 10475307
• 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/10475307
• 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; antagonist; 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 艾滋病毒携带者(PWH)患心血管疾病的风险大约是 艾滋病毒阴性的个人，这不能用传统的风险因素解释，尽管有效，但仍存在 抗逆转录病毒治疗。一些证据表明，巨细胞病毒(CMV)是一种几乎普遍存在的混合感染 PWH的许多亚组可能与心血管疾病风险增加有关。然而，仅CMV血清阳性(即 抗CMV抗体的存在)不足以作为心血管疾病的预测指标，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。 在PWH中，虽然CMV被认为是重要的，但其在PWH中对CVD的具体贡献尚不清楚。当前 关于巨细胞病毒对心血管疾病的贡献的知识在几个方面是有限的：1)很少有人体研究评估 外周血循环抗巨细胞病毒T细胞与普遍存在的动脉粥样硬化2)数据匮乏 人类动脉粥样硬化斑块中是否存在CMV特异性T细胞。3)目前还没有 建立可靠的动物模型，研究病毒特异性T细胞在斑块中的渗透情况。我们已经证明了 共表达表面标志CX3CR1、GPR56和CD57(即C-G-C)的CD4+T细胞主要是CMV- 具体的。我们还发现代谢性疾病的PWH患者血液中C-G-C+CD4+T细胞增多。 和亚临床动脉粥样硬化。趋化因子受体CX3CR1在CMV特异性T细胞上的高表达 并将细胞运输到激活的内皮细胞，我们假设膨胀的抗CMV C-G-C+CD4+T细胞招募 通过CX3CR1致炎的内皮细胞是PWH亚临床动脉粥样硬化的主要驱动力。我是一名医生 精通免疫学和微生物发病机制的科学家，受过传染病方面的培训。我量身定制的职业生涯 发展计划将通过体验式、指导性和专业性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)临床和翻译研究；(4)人-鼠嵌合体 模型；(5)负责任的研究行为。与一个具有艾滋病毒专业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。在目标1中，我们将检验外周C-G-C+CD4+T细胞是CMV特异性的和相关的假设 有亚临床动脉粥样硬化的PWH。在目标2中，我们将检验斑块渗入C-G-C+CD4+的假设 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中的募集 炎症动脉粥样硬化的CMV特异性C-G-C+CD4+T细胞依赖于CX3CR1。完成这些特定的 AIMS将增加我们对CMV是否在PWH的CVD中起重要作用的了解。随着工程的完成 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 尖端免疫学。完成这项K23奖项将使我过渡为一名独立的 心脏免疫学领域的内科科学家，专注于病毒特异性免疫反应。