Mechanisms of Frailty in HIV-1 Infection

描述(申请人提供)：虚弱是衰老的一种并发症，由多种系统的失调引起，导致发病率增加，并最终增加死亡率。在感染人类免疫缺陷病毒1型(HIV-1)的患者中，虚弱的患病率是年龄匹配的HIV阴性对照组的3倍，并且比HIV-1阴性老年患者的预期提前20年。对我们小组正在进行的脆弱性研究的初步分析表明，在接受高效抗逆转录病毒疗法(HAART)治疗的HIV-1感染者中，免疫激活、免疫衰老和临床脆弱性之间存在以前未知的关联。这项建议的全球目标是了解HIV-1感染的虚弱个体免疫功能障碍的机制。为了评估这一全球目标，我们将利用HIV-1感染的虚弱个体和匹配的HIV-1感染的非虚弱对照的储存样本来1)确定慢性巨细胞病毒(CMV)合并感染通过巨细胞病毒抗原刺激T细胞在艾滋病毒相关脆弱中的作用；2)通过血浆脂多糖(LPS)和可溶性激活标志物CD14(SCD14)研究微生物肠道易位在HIV相关脆弱中的作用；3)利用人类T细胞基因芯片分析人类T细胞基因的表达模式，以确定与HIV-1感染者的脆弱表型相关的潜在基因表达模式。这项拟议的研究将首次分析慢性CMV感染、微生物易位和T细胞中的多态性在HIV-1相关脆弱性发展中的作用。这一结果将对诊断、治疗和预防HIV-1感染者和非感染者的脆弱性具有重要的临床意义。

DESCRIPTION (provided by applicant): Frailty is a complication of aging resulting from a dysregulation of multiple systems leading to increased morbidity, and ultimately increased mortality. The prevalence of frailty is 3-fold higher in human immunodeficiency virus type-1 (HIV-1) infected patients than age-matched HIV-negative controls, and occurs 20 years earlier than would be expected in HIV-1-negative aging patients. Preliminary analyses of ongoing studies of frailty by our group suggest a previously unrecognized association between immune activation, immune senescence, and clinical frailty in HIV-1-infected persons treated with highly-active antiretroviral therapy (HAART). The global aim of this proposal is to understand the mechanisms of immune dysfunction in HIV-1-infected frail individuals. To evaluate the global aim, we will use stored samples from HIV-1 infected frail individuals and matched HIV-1 infected non-frail controls to 1) Determine the role of chronic cytomegalovirus (CMV) co-infection in HIV-related frailty through CMV-antigen stimulation of T-cells 2) Investigate the role of microbial gut translocation in HIV-related frailty through plasma lipopolysaccharide (LPS) and soluble activation marker CD14 (sCD14) and 3) Use microarray analysis of human T-cell genes to identify potential gene expression patterns associated with the frail phenotype in HIV-1 infected persons. The proposed research will provide the first analysis of the role of chronic CMV infection, microbial translocation, and polymorphisms in T- cells in the development of HIV-1-related frailty. The results will have significant clinical implications in efforts to diagnose, treat, and prevent frailty in HIV-1-infected and uninfected individuals.