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 由于引入了抗逆转录病毒疗法（ART），艾滋病现在很少见 - 相反，艾滋病毒具有 成为工业界大部分地区的慢性疾病。 50岁以上的患者（PWH）化妆 在所有感染者中，几乎一半（仅在美国> 60万人），而且他们的人数正在增加。但 这些人没有治愈：PWH以高于比率高的情况经历多个合并条件 与未感染年龄匹配的人相比，生活。这些与HIV相关的非AIDS条件（HANA）导致 类似于明显/加速的身体和认知功能缺陷的过早准确性 衰老表型。艾滋病毒和衰老伴随着炎症和免疫功能下降，表明 两者都可以在PWH中的衰老加剧的衰老方面进行潜在的和/或驱动。持续性巨细胞病毒（CMV） 在免疫衰老和与年龄相关的感染中也暗示了感染，但是存在明显的间隔 人的变化和对CMV的控制不完整的衰老。有限的数据表明 PWH中看到的过早的“衰老”表型仅在与CMV共感染的人中发现，但控制 PWH中的CMV仍然知之甚少。因此，CMV可能是老年艾滋病毒+疾病的驱动力 个体，具有分层和预测价值的标记，或者都不是。我们已经开发了一系列测试 测量CMV病毒载荷，抗CMV NK，T和B细胞免疫史的全身注射水平， 并发现<50％的HIV阴性参与者表现出抗CMV中和AB（NAB），但> 90％ 艾滋病毒+年龄匹配的参与者发展了NAB。我们假设抗CMV NAB产生是一个直接功能 急性HIV感染期间或可能在后期的CMV负载和复制。我们也有 开发并验证了上肢屈曲（UEF）测试，加上认知测试，可以提供 简单评估脆弱，运动，心血管和认知功能，所有这些都提供了深度 对生活质量（QOL）和老年综合征的功能见解。我们寻求使用这些工具来评估 CMV和CMV相关的炎症作为生物标志物在预测功能下降的轨迹中的影响 在艾滋病毒+患有衰老的人。我们的假设是具有CMV重新激活迹象的PWH（病毒载荷，高 抗CMV NAB，T和NK细胞激活的水平）在延长和高CMV重新激活中 急性艾滋病毒疾病和/或在其后果中，具有广泛的免疫和炎症异常， 这使它们容易综合的慢性病和老年综合症，例如脆弱，流动性/跌倒 并降低了认知能力。我们将通过免疫和炎症的多元分析来检验这一假设 三个观察者（一个前瞻性）和一种抗CMV药物治疗的介体和老年评估 队列，包括两个性别。这项工作将剖析CMV，炎症和减少的关系 艾滋病毒+个人的整体健身，脆弱和加速和/或失败的老龄化，可以提供基础 为了对艾滋病毒的老年人进行更广泛的抗CMV治疗，以改善其健康状况。