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

描述（由申请人提供）：CD4+ t细胞是有效适应性免疫反应发展的核心；然而，像其他淋巴细胞一样，CD4+ t细胞也容易衰老。衰老的t细胞的特征是端粒缩短，增殖能力降低，细胞因子产生改变，信号通路和许多其他功能缺陷。基于我们的初步数据，我们假设HIV-1感染导致初始CD4+ t细胞区加速衰老。使用CD31将初始CD4+ t细胞分裂为CD27+CD45RA+CD31+和CD27+CD45RA+CD31-亚群，我们已经证明HIV-1感染与(a)两个亚群内细胞绝对数量(b)两个亚群内端粒长度以及(c) CD27+CD45RA+CD31+亚群内端粒酶活性的加速下降有关。的确，根据这些标准，HIV-1感染的、未经抗逆转录病毒治疗的男性的初始CD4+ t细胞区室与比他们大20至30岁的血清阴性男性非常相似。尽管CD27+CD45RA+CD31+群体代表了增殖史最少的初始CD4+ t细胞亚群，但端粒缩短在该亚群中是显著的，这表明除了增加t细胞周转率之外，其他机制可能起作用。如果像衰老一样，端粒变短与功能能力下降有关，那么幼稚的CD4+ t细胞区室的衰老可能对个体产生有效免疫反应的能力产生深远的影响，不仅对HIV-1，而且对其他病原体、疫苗和肿瘤也有影响。此外，正如我们的初步数据所表明的那样，如果有充分证据表明，幼稚CD4+ t细胞的年龄相关缺陷与HIV- 1感染对该细胞室的影响协同作用，这可能有助于观察到老年人疾病进展率的增加。如果不能被ART逆转，这些缺陷也可能对HIV-1感染、ART治疗的个体的成功衰老产生重要影响。拟议的研究将提供更全面的理解短端粒在这个初始CD4+ t细胞区室（Aim 1）的功能意义，这种缩短背后的机制（Aim 2）和抗逆转录病毒治疗逆转这些缺陷的潜力（Aim 3）。

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.