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: 10655601
• 负责人: Celestine N Wanjalla
• 金额: $ 18.33万
• 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/10655601
• 关键词: ADGR1 gene; 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; Cell Separation; Cells; Cellular Immunity; Chimera organism; Chronic; Clinical Research; Collaborations; Communicable Diseases; Coronary artery; Cytomegalovirus; Data; Development; Development Plans; Disease; Disease Pathway; Endothelium; Engraftment; Epidemiology; Epitopes; Event; Foundations; Funding; HIV; HIV Seronegativity; HIV/AIDS; Home; Human; Image; Immune; Immune response; Immunology; Implant; Individual; Infiltration; Inflammation; Infrastructure; Institution; Intervention Trial; Intravenous; Knowledge; Label; Leadership; Ligands; Linear Regressions; Link; Measures; Mentored Clinical Scientist Development Program; 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; Science; Scientist; Structure of thyroid parafollicular cell; Subgroup; Surface; T memory cell; T-Lymphocyte; T-cell receptor repertoire; Tennessee; Testing; Tissues; Training; Translational Research; United States National Institutes of Health; Virus; Work; X-Ray Computed Tomography; alpha-beta T-Cell Receptor; antagonist; antiretroviral therapy; cardiovascular disorder risk; cardiovascular risk factor; career development; chemokine receptor; co-infection; cohort; health difference; high risk; immunomodulatory strategy; 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.

项目概要 与艾滋病毒感染者 (PWH) 相比，患心血管疾病 (CVD) 的风险大约高出 2 倍 HIV 阴性个体，这种情况无法用传统的危险因素来解释，并且尽管采取了有效的措施，这种情况仍然存在 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合并感染， PWH 的许多亚组可能与 CVD 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 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 尽管 CMV 被认为很重要，但其对 PWH 中 CVD 的具体贡献尚不清楚。当前的 关于 CMV 对 CVD 的影响的知识在以下几个方面受到限制： 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）相关数据较少 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 可靠的动物模型来研究病毒特异性 T 细胞渗入斑块的情况。我们已经证明 共表达表面标记 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，患有代谢性疾病的感染者血液中的 C-G-C+ CD4+ T 细胞增多 和亚临床动脉粥样硬化。由于趋化因子受体 CX3CR1 在 CMV 特异性 T 细胞上高表达 并将细胞转运至活化的内皮细胞，我们假设膨胀的抗 CMV C-G-C+ CD4+ T 细胞被招募 通过 CX3CR1 导致内皮细胞发炎是 PWH 中亚临床动脉粥样硬化的主要驱动因素。我是一名医生 精通免疫学和微生物发病机制并接受过传染病培训的科学家。我量身定制的职业生涯 发展计划将通过以下方面的体验式、教学式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)临床及转化研究； (4)人鼠嵌合体 模型； (5) 负责任地进行研究。拥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、CVD、动脉粥样硬化，我将完成以下工作 目标。在目标 1 中，我们将检验以下假设：外周 C-G-C+ CD4+ T 细胞具有 CMV 特异性且相关 PWH 中患有亚临床动脉粥样硬化。在目标 2 中，我们将检验以下假设：斑块浸润 C-G-C+ CD4+ T 细胞具有 CMV 特异性。在目标 3 中，我们将使用小鼠模型来检验以下假设：循环细胞的募集 CMV 特异性 C-G-C+ CD4+ T 细胞对发炎粥样斑块的作用是 CX3CR1 依赖性的。完成这些具体 目的将增加我们对 CMV 是否在 PWH CVD 中发挥重要作用的了解。随着完成 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 最前沿的免疫学。完成这个 K23 奖项将使我能够过渡为独立人士 心脏免疫学领域的医师科学家，专注于病毒特异性免疫反应。

项目成果

Distinct CD3 + CD14 + T Cell-Monocytes are dynamic complexes that harbor HIV and are increased with glucose intolerance.

独特的 CD3 CD14 T 细胞-单核细胞是携带 HIV 的动态复合物，并随着葡萄糖不耐受而增加。

• DOI: 10.1101/2023.04.24.538020
• 发表时间: 2023
• 期刊: bioRxiv : the preprint server for biology
• 作者: Wanjalla,CelestineN;Simmons,Joshua;Oakes,Jared;Zhang,Xiuqi;Nochowicz,Cindy;Priest,Stephen;Bailin,SamuelS;Warren,ChristopherM;Mashayekhi,Mona;Beasley,HeatherK;Wang,Jian;Meenderink,Leslie;Sheng,Quanhu;Stolze,Joey;Gangula,Ram
• 通讯作者: Gangula,Ram

Immune Cell Activation in Obesity and Cardiovascular Disease.

• DOI: 10.1007/s11906-022-01222-4
• 发表时间: 2022-12
• 期刊: Current hypertension reports
• 影响因子: 5.6

A Practical Guide to Graduate School Interviewing for Historically Excluded Individuals

历史上被排除在外的个人研究生院面试实用指南

• DOI: 10.1152/ajpheart.00123.2023
• 发表时间: 2023
• 期刊: American Journal of Physiology-Heart and Circulatory Physiology
• 影响因子: 4.8
• 作者: Ransey, Elizabeth;Brookens, Shawna;Beasley, Heather K.;Marshall, Andrea;Marlin, Bianca J.;Rodriguez-Aliaga, Piere;Headley, Colwyn Ansel;Wanjalla, Celestine;Vazquez, Arnaldo Diaz;Murray, Sandra
• 通讯作者: Murray, Sandra