MicroRNAs and age-related immune dysfunction in HIV infection

描述（由申请人提供）：由于HAART治疗延长了患者的生存期，50岁以上的iv型感染者越来越多。衰老与免疫功能下降有关，包括胸腺输出量减少、t细胞增殖能力降低、原始CD4和CD8 t细胞频率降低、Tregs频率增加、B细胞和t细胞库收缩以及炎症基础水平增加。年龄相关的免疫功能下降的机制以及这些过程如何影响年龄增长的hiv感染者的免疫失调尚不清楚。microrna调节多种生物过程，包括细胞发育、分化、增殖、衰老和凋亡，并在免疫中发挥重要作用。mirna与秀丽隐杆线虫和小鼠的衰老过程有关，但它们在人类衰老中的作用尚未被探索。初步研究根据中年和老年受试者样本的miRNA表达谱确定了人类PBMC中年龄调节的miRNA。这些mirna中的一些是免疫功能的重要调节因子，并且先前在hiv感染个体的PBMC中显示出一个亚群失调。本研究将探讨mirna在HIV感染中年龄相关免疫功能障碍中的作用。我们的工作假设是，原始和中枢记忆t细胞亚群中miRNA调节的变化有助于免疫系统功能与年龄相关的下降，并且由于HIV、免疫激活或抗病毒药物毒性的影响，在HIV感染个体中加速。衰老免疫系统中mirna的动态调节可能协调一系列基因的表达，以保护t细胞免受与年龄相关的应激（即氧化应激、DNA损伤），但这种机制可能以免疫功能受损或失调为代价。该提案将研究三个具体目标：1)表征从青年、中年和老年人中分离的CD4和CD8幼稚T细胞亚群和记忆T细胞亚群中年龄调节的mirna，并确定HIV感染与未感染个体相比其表达谱的差异是否表明免疫系统加速衰老；2)确定t细胞亚群中年龄调节的mirna与免疫衰老标志物之间的关系；3)探索miR-223和其他年龄上调的mirna作为CD4 T细胞功能抑制因子的作用，促进HIV在静息CD4 T细胞中的潜伏期。这些研究将更好地了解衰老过程中免疫功能下降的机制，以及它们如何导致老年HIV感染患者的年龄相关免疫功能障碍。

DESCRIPTION (provided by applicant): There is a growing population of IV-infected people over the age of 50 due to prolonged survival on HAART. Aging is associated with a decline in immune functions that include decreased thymic output, reduced T-cell proliferative capacity, reduced frequency of naove CD4 and CD8 T-cells, increased frequency of Tregs, constricted B- and T-cell repertoire, and increased basal levels of inflammation. The mechanisms underlying age-related decline in immune function and how these processes influence immune dysregulation in HIV-infected individuals with increasing age are unknown. microRNAs regulate diverse biological processes including cell development, differentiation, proliferation, senescence, and apoptosis, and play important roles in immunity. miRNAs are implicated in aging processes in C. elegans and mice, but their role in human aging has not been explored. Preliminary studies identified age-regulated miRNAs in human PBMC based on miRNA expression profiling of samples from middle-aged versus elderly subjects. Several of these miRNAs are important regulators of immune function, and a subset were previously shown to dysregulated in PBMC from HIV-infected individuals. This proposal will investigate the role of miRNAs in age-related immune dysfunction in HIV infection. Our working hypothesis is that changes in miRNA regulation in naove and central memory T-cell subsets contribute to age-related decline in immune system function, and are accelerated in HIV-infected individuals due to effects of HIV, immune activation, or antiviral drug toxicities. Dynamic regulation of miRNAs in the aging immune system may coordinate expression of sets of genes to protect T-cells against age-related stresses (i.e. oxidative stress, DNA damage), but this mechanism may come at the cost of impaired or dysregulated immune function. This proposal will investigate three specific aims: 1) Characterize age-regulated miRNAs in CD4 and CD8 naive and memory T cell subsets isolated from young, middle-aged, and aged individuals and determine if differences in their expression profiles in HIV- infected compared to uninfected individuals suggest accelerated aging in the immune system; 2) Determine the association between age-regulated miRNAs in T-cell subsets and markers of immunological aging; 3) Explore the role of miR-223 and other age-upregulated miRNAs as suppressors of CD4 T cell function that promote HIV latency in resting CD4 T cells. These studies will provide a better understanding of mechanisms that underlie the decline in immune function that occurs during aging, and how they contribute to age-related immune dysfunction in older individuals with HIV infection. PUBLIC HEALTH RELEVANCE: This proposal will investigate the role of microRNAs n age-related immune dysfunction in HIV infection. The studies will provide a better understanding of mechanisms that underlie the decline in immune function that occurs with increasing age, and how they contribute to age-related immune dysfunction in older individuals with HIV infection.