MicroRNAs and age-related immune dysfunction in HIV infection

描述(由申请人提供)：由于在HAART上存活时间较长，50岁以上的IV感染者人数不断增加。衰老与免疫功能下降有关，包括胸腺输出减少，T细胞增殖能力降低，NAVE CD4和CD8 T细胞频率降低，Tregs频率增加，B和T细胞谱系收缩，基础炎症水平增加。与年龄相关的免疫功能下降的机制以及这些过程如何影响艾滋病毒感染者随年龄增长的免疫失调尚不清楚。MicroRNAs调控细胞发育、分化、增殖、衰老和细胞凋亡等多种生物学过程，在免疫中发挥重要作用。MiRNAs与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。根据中老年受试者样本的miRNA表达谱，初步研究确定了人PBMC中受年龄调节的miRNAs。其中几个miRNAs是免疫功能的重要调节因子，此前已有研究表明，HIV感染者的PBMC中有一个亚群调节失调。这项建议将调查miRNAs在HIV感染中与年龄相关的免疫功能障碍中的作用。我们的工作假设是，NAOVE和中央记忆T细胞亚群中miRNA调节的变化导致了与年龄相关的免疫系统功能下降，并由于HIV、免疫激活或抗病毒药物毒性的影响而在HIV感染者中加速。在衰老的免疫系统中，对miRNAs的动态调节可能会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(如氧化应激、DNA损伤)，但这一机制可能是以免疫功能受损或失调为代价的。这项建议将研究三个具体目标：1)表征从年轻、中年和老年个体分离的CD4和CD8幼稚和记忆T细胞亚群中受年龄调节的miRNAs，并确定它们在HIV感染者和未感染个体中的表达差异是否表明免疫系统加速衰老；2)确定T细胞亚群中受年龄调节的miRNAs与免疫衰老的标志物之间的关联；3)探索miR-223和其他年龄上调的miRNAs作为促进HIV潜伏期在静止的CD4T细胞中的CD4T细胞功能的作用。这些研究将更好地了解在衰老过程中免疫功能下降的机制，以及它们如何导致感染艾滋病毒的老年人的年龄相关免疫功能障碍。 公共卫生相关性：这项提案将调查微RNA在与年龄相关的免疫功能障碍中在艾滋病毒感染中的作用。这些研究将更好地了解随着年龄增加而出现的免疫功能下降的机制，以及它们如何导致感染艾滋病毒的老年人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.