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

HIV 和年龄对幼稚 CD4 T 细胞衰老的协同作用

• 批准号: 8310978
• 负责人: Beth Deirdre Jamieson-Karavodin
• 金额: $ 68.68万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-01 至 2015-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8310978
• 关键词: Activities of Daily Living; Age; Aging; Anti-Retroviral Agents; Area; CD4 Positive T Lymphocytes; Cancer Vaccines; Cell Aging; Cell Count; Cells; Clonal Expansion; Communicable Diseases; Data; Defect; Development; Disease Progression; Elderly; HIV; HIV-1; Health; Immune response; Immune system; Individual; Infection; Length; Lymphocyte; Neoplasms; Oxidative Stress; PECAM1 gene; Pathogenesis; Patients; Pluripotent Stem Cells; Population; Production; Recording of previous events; Research; Risk; Signal Pathway; T-Lymphocyte; T-Lymphocyte Subsets; Telomerase; Telomere Shortening; Testing; Vaccines; Viral Load result; age related; base; cytokine; insight; men; new therapeutic target; pathogen; peer; premature; repaired; research study; response; senescence; telomere; therapeutic target

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.

描述（由申请人提供）：CD 4 + T细胞是有效适应性免疫应答发展的核心;然而，与其他淋巴细胞一样，CD 4 + T细胞对细胞衰老敏感。衰老T细胞的特征在于端粒缩短、增殖能力降低以及细胞因子产生、信号传导途径和许多其他功能缺陷的改变。基于我们的初步数据，我们假设HIV-1感染导致幼稚CD 4 + T细胞区室内的加速衰老。使用CD 31将初始CD 4 + T细胞分为CD 27 + CD 45 RA + CD 31+和CD 27 + CD 45 RA + CD 31-亚群，我们已经表明HIV-1感染与以下各项的加速下降相关：（a）两个亚群内的细胞绝对数量（B）两个亚群内的端粒长度，和（c）CD 27 + CD 45 RA + CD 31+亚群内的端粒酶活性。实际上，根据这些标准，HIV-1感染、ART初治男性中的初治CD 4 + T细胞区室与年长他们20至30岁的血清阴性男性非常相似。虽然CD 27 + CD 45 RA + CD 31+群体代表了具有最少增殖史的初始CD 4 + T细胞亚群，但该亚群中的端粒缩短是显著的，这表明除了增加T细胞周转之外的机制可能是有效的。如果像在衰老中一样，较短的端粒与功能能力下降相关，则初始CD 4 + T细胞区室的衰老可能对个体产生有效免疫应答的能力产生深远影响，不仅对HIV-1，而且对其他病原体以及疫苗和肿瘤。此外，如我们的初步数据所示，如果幼稚CD 4 + T细胞中与年龄相关的缺陷与HIV- 1感染对该隔室的影响协同作用，这可能有助于观察到老年人疾病进展率增加。如果不被ART逆转，这些缺陷也可能对HIV-1感染者，ART治疗，个体的成功衰老具有重要意义。拟议的研究将提供一个更全面的理解较短的端粒在这个幼稚的CD 4 + T细胞室的功能意义（目标1），这种缩短背后的机制（目标2）和ART逆转这些缺陷的潜力（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，我们可以确定衰老的机制，这些机制可以通过治疗策略来提高HIV-1感染者和老年人的健康。