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.

摘要 由于联合抗逆转录病毒疗法（ART）的引入，艾滋病现在很罕见-相反，艾滋病毒已经 成为工业世界的一种慢性病。50岁以上的艾滋病毒感染者占 近一半的感染者（仅在美国就有超过60万人），而且他们的人数还在增加。但 这些人没有被治愈：PWH经历多种共病状况的比率高于， 与未受感染的年龄匹配的人相比。这些HIV相关的非艾滋病状况（HANA）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， 两者都可能增强和/或驱动PWH中的加速老化的方面。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，但它们之间存在显著的相互作用。 人的差异和不完全理解的控制CMV与老化。有限的数据表明， 在PWH中观察到的过早“衰老”表型仅见于CMV共感染者，但对照组中未发现CMV感染者。 CMV在PWH中的作用仍知之甚少。因此，CMV可能是老年HIV+患者残疾的驱动因素 个体，具有分层和预测价值的标记，或者两者都不是。我们开发了一系列测试， 测量CMV病毒载量、抗CMV NK、T和B细胞免疫力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+年龄匹配的参与者产生nAb。我们假设抗CMV nAb的产生是一个直接的功能， 在急性HIV感染期间，也可能在急性HIV感染后，CMV载量和复制。我们还 开发并验证了上肢屈曲（UEF）测试，再加上认知测试，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。我们试图利用这些工具来评估 巨细胞病毒和巨细胞病毒相关炎症作为生物标志物预测功能下降轨迹的影响 艾滋病病毒携带者的年龄。我们的假设是，PWH与CMV再激活的迹象（病毒载量，高 抗CMV nAb、T细胞和NK细胞活化水平）在治疗期间经历了长时间的高CMV再活化。 急性HIV疾病和/或其后遗症，伴有广泛的免疫和炎症异常， 使他们容易患上严重慢性病和老年综合症，如虚弱、行动不便/福尔斯 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药物治疗中的介质和老年评估 组群，包括两性。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、虚弱和加速和/或不成功的衰老，并可提供依据 对感染艾滋病毒的老年人进行更广泛的抗CMV治疗，以改善他们的健康状况。