Synergistic effects of HIV and age on naive CD4+ T-cell senescence

描述(由申请人提供)：CD4+T细胞是发展有效的适应性免疫反应的中心；然而，像其他淋巴细胞一样，CD4+T细胞容易受到细胞衰老的影响。衰老T细胞的特征是端粒缩短，增殖能力降低，以及细胞因子产生、信号通路和许多其他功能缺陷的改变。根据我们的初步数据，我们假设HIV-1感染会导致幼稚的CD4+T细胞内加速衰老。使用CD31将初始的CD4+T细胞分为CD27+CD45RA+CD31+和CD27+CD45RA+CD31-亚群，我们发现HIV-1感染与(A)两个亚群内的细胞绝对数(B)两个亚群内的端粒长度以及(C)CD27+CD45RA+CD31+亚群内的端粒酶活性的加速下降有关。事实上，根据这些标准，感染HIV-1、天真的男性体内幼稚的CD4+T细胞隔间与比他们年长20至30岁的血清阴性男性非常相似。虽然CD27+CD45RA+CD31+人群代表了增殖史最少的幼稚的CD4+T细胞亚群，但端粒缩短在这个亚群中是显著的，这表明除了增加T细胞周转率之外的其他机制可能是有效的。如果像在衰老中一样，端粒变短与功能能力下降相关，那么幼稚的CD4+T细胞隔间的衰老可能会对个体建立有效免疫反应的能力产生深远影响，不仅是对艾滋病毒-1，而且对其他病原体，以及疫苗和肿瘤。此外，如果我们的初步数据表明，幼稚的CD4+T细胞中与年龄相关的缺陷与HIV-1感染对这一间隔的影响协同作用，这可能有助于观察到老年人疾病进展的速度加快。如果不能通过抗逆转录病毒治疗逆转，这些缺陷也可能对感染艾滋病毒-1并接受抗逆转录病毒治疗的人的成功衰老产生重要影响。拟议的研究将提供一个更全面的了解在这个幼稚的CD4+T细胞隔间中较短的端粒的功能意义(目标1)，这种缩短背后的机制(目标2)以及ART逆转这些缺陷的可能性(目标3)。 公共卫生相关性：通过了解年龄和HIV-1如何影响免疫系统，我们可以确定衰老机制，这些机制可以被提高HIV-1感染者和老年人健康的治疗策略所针对。

DESCRIPTION (provided by applicant): CD4+ T-cells are central to the development of effective adaptive immune responses; however, like other lymphocytes, CD4+ T-cells are susceptible to cellular senescence. Senescent T-cells are characterized by shortened telomeres, reduced proliferative capacity, as well as altered cytokine production, signaling pathways and a host of other functional defects. Based on our preliminary data, we hypothesize that HIV-1 infection leads to accelerated senescence within the naive CD4+ T-cell compartment. Using CD31 to divide the naive CD4+ T-cells into CD27+CD45RA+CD31+ and CD27+CD45RA+CD31- subpopulations, we have shown that HIV-1 infection is associated with an accelerated decline in (a) the absolute number of cells within both subsets (b) telomere length within both subsets, and (c) telomerase activity within the CD27+CD45RA+CD31+ subset. Indeed, by these criteria, the naive CD4+ T-cell compartment in HIV-1 infected, ART naive, men closely resembles that of seronegative men 20 to 30 years their senior. Although the CD27+CD45RA+CD31+ population represents the naive CD4+ T-cell subset with the least proliferative history, telomere shortening in this subset is significant, suggesting that mechanisms other than increased T-cell turnover may be operative. If, as in aging, the shorter telomeres correlate with decreased functional capacity, the senescence of the naive CD4+ T-cell compartment may have a profound impact on the ability of the individual to mount effective immune responses, not only to HIV-1, but also to other pathogens, as well as vaccines and neoplasms. Moreover, if the well-documented age-related deficits in naive CD4+ T-cells synergizes with the effects of HIV- 1 infection on this compartment, as suggested by our preliminary data, this may contribute to the observed increased rate of disease progression in older persons. If not reversed by ART, these defects could also have important implications for the successful aging of HIV-1 infected, ART treated, individuals. The proposed studies will provide a more comprehensive understanding of the functional significance of the shorter telomeres in this naive CD4+ T-cell compartment (Aim 1) the mechanisms behind this shortening (Aim 2) and the potential for ART to reverse these defects (Aim 3). PUBLIC HELATH RELEVANCE: By understanding how age and HIV-1 impact the immune system, we may identify mechanisms of aging that can be targeted by therapeutic strategies increasing the health of both HIV-1 infected individuals and the elderly.