T memory stem cell aging in HIV-1 infection

产品说明：HIV-1感染会导致一种慢性疾病，这种疾病与免疫加速老化的迹象有关，即使现有的抗逆转录病毒联合治疗有效抑制了活跃的病毒复制。这种生理老化过程的加速在年龄>50岁的HIV-1感染者的不断增长的人群中最为明显，并且预计到2015年将占美国和其他西方国家全部HIV-1患者人群的一半以上。然而，对HIV-1感染中免疫系统过早衰老的机制还不清楚，也没有具体的临床干预措施。 在这一点上，可以延缓这一特定患者群体的加速衰老。衰老的干细胞假说假定衰老主要反映了体干细胞的频率和功能的下降，体干细胞能够再生和重新填充成熟的组织细胞。免疫老化的表型和功能迹象似乎只发生在干细胞介导的组织再生耗尽和有缺陷的时候。最近，已经鉴定出一种新的淋巴细胞干细胞群体，其代表抗原特异性记忆T细胞的最早发育阶段，并且在整个生命周期中持续存在以重新填充所有已知的记忆T细胞亚群。本申请的一个中心假设是，这种称为“T记忆干细胞”的新型干细胞群的加速老化代表了HIV-1感染期间所有随后的过早细胞免疫衰老迹象出现的原始事件。为了研究这个假设，我们将首先关注一个详细的 使用细胞、分子、遗传和功能免疫学测定，评估不同年轻和老年HIV-1感染人群中T记忆干细胞（包括HIV-1特异性T记忆干细胞）的功能和分子特征（具体目标1）。由于T记忆干细胞的发育程序是由干细胞特异性分子途径控制的，我们随后将研究是否可以通过增强干细胞特异性功能程序的药物来操纵和改善HIV-1患者T记忆干细胞的衰老特征。为此目的，我们将使T记忆干细胞暴露于wnt/β-连环蛋白途径的药物活化剂，该途径是一种涉及调节干细胞的不对称细胞分裂、多能性/多能性和稳态增殖的遗传学保守的分子程序，并使用一组已建立的测定来评估所得的功能效应（具体目标2）。虽然T记忆干细胞对免疫衰老的作用是在HIV-1感染的背景下研究的，但我们的研究可能超越HIV-1感染，并适用于与过早免疫衰老相关的其他疾病背景。

DESCRIPTION: Infection with HIV-1 causes a chronic medical condition that is associated with signs of accelerated immune aging, even when active viral replication is effectively suppressed with existing antiretroviral combination therapy. This acceleration of the physiologic aging process is most obvious in the growing population of HIV-1 infected persons who are >50 years old and projected to account for more than half of the entire HIV-1 patient population in the US and other western countries by 2015. Yet, mechanisms responsible for premature immune senescence in HIV-1 infection are insufficiently understood, and no specific clinical interventions are available at this point that may retard accelerated aging in this specific patient population. The stem cell hypothesis of aging postulates that aging predominantly reflects a decline in the frequency and function of somatic stem cells, which are able to regenerate and repopulate mature tissue cells. Phenotypic and functional signs of immune aging only seem to occur when the stem cell-mediated regeneration of tissues is exhausted and defective. Recently, a new population of lymphocellular stem cells has been identified that represents the earliest developmental stage of antigen-specific memory T cells and persist throughout lifetime to repopulate all known memory T cell subsets. A central hypothesis of this application is that accelerated aging of this novel stem cell population, termed "T memory stem cells", represents the original event from which all subsequent signs of premature cellular immune senescence during HIV-1 infection arise. To investigate this hypothesis, we will initially focus on a detailed assessment of functional and molecular characteristics of T memory stem cells, including HIV-1-specific T memory stem cells, in different populations of young and elderly HIV-1 infected persons, using cellular, molecular, genetic and functional immunologic assays (specific aim 1). Since developmental programs in T memory stem cells are governed by stem cell-specific molecular pathways, we will subsequently investigate whether the aging profile of T memory stem cells from HIV-1 patients can be manipulated and ameliorated through pharmaceutical agents that enhance stem-cell specific functional programs. For this purpose, we will expose T memory stem cells to pharmaceutical activators of the wnt/beta- catenin pathway, a phylogenetically conserved molecular program involved in regulating asymmetric cell division, multi-/pluri-potency and homeostatic proliferation of stem cells, and evaluate the resulting functional effects using a panel of established assays (specific aim 2). Although the role of T memory stem cells for immune aging is investigated in the context of HIV-1 infection in this application, our studies may go beyond HIV-1 infection and be applicable in alternative disease contexts associated with premature immune aging.