The role of CMV in HIV-associated accentuated aging

CMV 在 HIV 相关的加速衰老中的作用

• 批准号: 10760596
• 负责人: JANKO Z. NIKOLICH
• 金额: $ 67.25万
• 依托单位: UNIVERSITY OF ARIZONA
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2028-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10760596
• 关键词: Acceleration; Acquired Immunodeficiency Syndrome; Acute; Adult; Age; Aging; Antigens; Automobile Driving; Autonomic Dysfunction; B-Lymphocytes; Biological Markers; Biological Response Modifiers; CD28 gene; CD8-Positive T-Lymphocytes; CD8B1 gene; Cardiac; Cardiovascular Physiology; Chronic; Chronic Disease; Chronic Kidney Failure; Clinical Trials; Cognitive; Cognitive deficits; Collaborations; Coupled; Cytomegalovirus; Cytomegalovirus Infections; DNA; Data; Disease; Elderly; Exhibits; Future; Geriatric Assessment; HIV; HIV Infections; HIV Seronegativity; Hyperlipidemia; Hypertension; Immune; Immune response; Immunity; Immunologic Markers; Impaired cognition; Impairment; Individual; Industrialization; Inflammaging; Inflammation; Inflammation Mediators; Inflammatory; Lead; Life; Life Expectancy; Link; Longevity; Malignant Neoplasms; Measures; Mediating; Mental Depression; Motor; Multivariate Analysis; NK Cell Activation; Natural Killer Cells; Neutralization Tests; Non-Insulin-Dependent Diabetes Mellitus; Participant; Persons; Pharmacotherapy; Phenotype; Predictive Value; Premature aging syndrome; Production; Publications; Quality of life; Questionnaires; Recording of previous events; Role; SF-36; Sampling; Syndrome; T-Lymphocyte; T-Lymphocyte Subsets; Testing; Tissues; Upper Extremity; Variant; Viral; Viral Load result; Work; age related; antiretroviral therapy; cell motility; cognitive ability; cognitive function; cognitive testing; cohort; comorbidity; cytokine; disability; exhaustion; experience; experimental study; falls; fitness; frailty; functional decline; functional status; healthspan; immune function; improved; inhibitor; insight; mortality; multimodality; multiple chronic conditions; neutralizing antibody; premature; prospective; response; sensor; seropositive; sex; systemic inflammatory response; tool; vascular inflammation

ABSTRACT Due to the introduction of combined antiretroviral therapy (ART), AIDS is now rare - instead HIV has become a chronic disease in much of the industrial world. Persons over 50 with controlled HIV (PWH) make up nearly half of all infected individuals (>0.6M people in the US alone) and their numbers are increasing. But these people are not cured: PWH experience multiple comorbid conditions at rates higher than, and earlier in life compared to, uninfected age-matched persons. These HIV-associated non-AIDS conditions (HANA) lead to premature accumulation of physical and cognitive functional deficits that resemble a pronounced/ accelerated aging phenotype. Inflammation and immune function decline accompany both HIV and aging, suggesting that both could potentiate and/or drive aspects of exacerbated aging in PWH. Persistent cytomegalovirus (CMV) infection has been implicated in immune aging and age-related inflammation too, but there are significant inter- person variations and an incomplete understanding of control of CMV with aging. Limited data suggests that the premature “aging” phenotype seen in PWH is only found in those co-infected with CMV, but the control of CMV in PWH remains poorly understood. Therefore, CMV could be a driver of disabilities in older HIV+ individuals, a marker with stratifying and predictive value, or neither. We have developed a battery of tests to measure CMV viral load, anti-CMV NK, T and B cell immunity, and concurrent levels of systemic inflammation, and have found that while <50% of HIV-negative participants exhibit anti-CMV neutralizing Ab (nAb), >90% HIV+ age-matched participants develop nAb. We hypothesize that anti-CMV nAb production is a direct function of CMV load and replication during, and maybe also in the aftermath, of the acute HIV infection. We have also developed and validated the upper extremity flexion (UEF) test that, coupled with cognitive testing, can provide simultaneous assessment of frailty, motility, cardiovascular and cognitive function, all of which provide deep functional insight into quality of life (QOL) and geriatric syndromes. We seek to use these tools to evaluate the impact of CMV and CMV-associated inflammation as biomarkers in predicting trajectories of functional decline in HIV+ individuals with aging. Our hypothesis is that PWH with signs of CMV reactivation (viral loads, high levels of anti-CMV nAb, T and NK cell activation) experienced prolonged and high CMV reactivation during acute HIV disease and/or in its aftermath, with a broad spectrum of immune and inflammatory abnormalities, that predispose them for aggravated chronic conditions and geriatric syndromes such as frailty, mobility/falls and reduced cognitive ability. We will test this hypothesis by multivariate analysis of immune and inflammatory mediators and geriatric assessment in three observational (one prospective) and one anti-CMV drug treatment cohort, including both sexes. This work will dissect the relationship between CMV, inflammation and reduced overall fitness, frailty and accelerated and/or unsuccessful aging in HIV+ individuals and could provide basis for broader anti-CMV treatment of older adults with HIV to improve their healthspan.

抽象的 由于联合抗逆转录病毒疗法（ART）的引入，艾滋病现在已经很少见了，相反，艾滋病毒已经很少见了。 成为许多工业世界的慢性病。 50 岁以上艾滋病毒控制者 (PWH) 的构成 近一半的感染者（仅在美国就有超过 60 万人），而且感染人数还在增加。但 这些人没有被治愈：PWH 经历多种合并症的比率高于并且更早 与未感染的同龄人相比。这些与 HIV 相关的非艾滋病病症 (HANA) 会导致 身体和认知功能缺陷的过早积累，类似于明显/加速的 衰老表型。炎症和免疫功能下降伴随着艾滋病毒和衰老，这表明 两者都可能加剧和/或推动艾滋病患者老龄化加剧。持续性巨细胞病毒（CMV） 感染也与免疫衰老和年龄相关炎症有关，但也存在显着的相互关系 个体差异以及对 CMV 随衰老的控制的不完全理解。有限的数据表明 PWH 中出现的过早“衰老”表型仅见于同时感染 CMV 的患者，但控制 感染后感染者中的巨细胞病毒 (CMV) 目前仍知之甚少。因此，CMV 可能是老年 HIV+ 患者残疾的一个驱动因素 个体、具有分层和预测价值的标记，或者两者都没有。我们开发了一系列测试 测量 CMV 病毒载量、抗 CMV NK、T 和 B 细胞免疫以及全身炎症的并发水平， 并发现虽然 <50% 的 HIV 阴性参与者表现出抗 CMV 中和抗体 (nAb)，但 >90% HIV+ 年龄匹配的参与者会产生 nAb。我们假设抗 CMV nAb 的产生是直接功能 急性 HIV 感染期间以及之后的 CMV 负载和复制。我们还有 开发并验证了上肢屈曲（UEF）测试，该测试与认知测试相结合，可以提供 同时评估虚弱、运动、心血管和认知功能，所有这些都提供了深入的 对生活质量 (QOL) 和老年综合征的功能性洞察。我们寻求使用这些工具来评估 CMV 和 CMV 相关炎症作为生物标志物对预测功能衰退轨迹的影响 艾滋病病毒感染者随着年龄的增长。我们的假设是，PWH 具有 CMV 重新激活的迹象（病毒载量、高 抗 CMV nAb、T 和 NK 细胞激活水平）经历了长时间且高的 CMV 再激活 急性艾滋病毒疾病和/或其后果，伴有广泛的免疫和炎症异常， 使他们容易患上慢性病和老年综合症，例如虚弱、行动不便/跌倒 以及认知能力下降。我们将通过免疫和炎症的多变量分析来检验这一假设 三种观察性（一种前瞻性）和一种抗 CMV 药物治疗中的中介因素和老年评估 队列，包括男女。这项工作将剖析 CMV、炎症和减少之间的关系 HIV+ 个体的整体健康状况、虚弱状况以及加速和/或不成功的衰老，可以提供依据 对感染艾滋病毒的老年人进行更广泛的抗巨细胞病毒治疗，以延长他们的健康寿命。