A new model of accelerated immune aging in HIV-infected drug users

产品说明：对艾滋病毒感染者采用高效抗逆转录病毒疗法，使艾滋病毒感染从致命疾病转变为可控制的疾病。然而，最近的证据表明，用HAART成功治疗的HIV感染患者以加速的速度发展与年龄相关的病理，包括心血管疾病、神经变性和癌症。许多接受HAART治疗的HIV感染患者也表现出持续免疫激活和加速免疫衰老的迹象，在年轻时积累了高水平的终末分化（衰老）CD 28记忆T细胞。类似的过早衰老综合征发生在慢性阿片类药物和兴奋剂使用者身上，他们发展出多系统退行性疾病，并伴有免疫激活症状。我们寻求对将HIV感染和药物滥用与慢性免疫激活联系起来的共同途径的分子洞察力，以开发旨在减缓加速免疫衰老和增强HIV感染吸毒者健康范围的新疗法。 我们最近发现NAD+依赖性脱乙酰酶SIRT 1是HIV感染中免疫激活的关键调节因子。SIRT 1是酵母sir 2酶的人类同源物，与酵母和蠕虫的寿命延长有关。将SIRT 1与HIV感染吸毒者的加速免疫衰老联系起来的证据有三个方面：1）我们发现SIRT 1活性受到HIV反式激活因子达特的抑制，这一过程导致下游SIRT 1靶点（如感染T细胞中的免疫刺激转录因子NF-κ B）的乙酰化增强。2)在未发表的初步研究中，我们发现SIRT 1蛋白表达在CD 28衰老记忆T细胞中丢失，这一发现与这些细胞的代谢状态改变（糖酵解增强）有关。3)Eric Nestler博士的实验室表明，可卡因是一种强大的兴奋剂，它激活了大脑中神经核的SIRT 1表达，从而引发基因表达的改变和药物奖励的增强。 在这里，我们建议测试艾滋病毒和滥用药物通过重新编程T细胞的转录和代谢谱协同加速免疫衰老的模型。我们将在一个新的T细胞衰老的体外系统中测试这个模型，方法是在衰老的T细胞中加入滥用药物（兴奋剂、阿片类药物），有或没有HIV达特。我们还将开发新技术来测量从患者分离的原代T细胞中免疫活化和代谢的关键标志物。特别强调SIRT 1和下游转录因子NF-κ B、FoxO 3A和HIF-1 α的翻译后修饰。我们希望我们的研究将通过建立艾滋病毒，滥用物质和衰老生物学途径之间的新联系，改变我们对艾滋病毒感染吸毒者免疫衰老的理解。

DESCRIPTION: The introduction of highly active antiretroviral therapy (HAART) in HIV-infected patients transformed HIV infection from a fatal condition into a manageable disease. However, recent evidence indicates that HIV- infected patients treated successfully with HAART develop age-associated pathologies at an accelerated rate, including cardiovascular disease, neurodegeneration and cancer. Many HIV-infected patients on HAART also show signs of persistent immune activation and accelerated immune aging with high levels of terminally differentiated (senescent) CD28- memory T cells accumulating at a young age. A similar premature aging syndrome occurs in chronic opiate and stimulant users who develop multi-system degenerative diseases in conjunction with symptoms of immune activation. We seek molecular insight into shared pathways linking HIV infection and drug abuse with chronic immune activation to develop novel therapies designed to slow accelerated immune aging and enhance the health span of HIV-infected drug users. We recently identified the NAD+-dependent deacetylase SIRT1 as a critical regulator of immune activation in HIV infection. SIRT1, a human homologue of the yeast sir2 enzyme, has been linked to prolonged lifespan in yeast and worms. The evidence that links SIRT1 to accelerated immune aging in HIV-infected drug users is threefold: 1) We showed that SIRT1 activity is inhibited by the HIV transactivator Tat, a process that leads to enhanced acetylation of downstream SIRT1 targets such as the immune stimulatory transcription factor NF-kappaB in infected T cells. 2) In unpublished preliminary studies, we find that SIRT1 protein expression is lost in CD28- senescent memory T cells, a finding tied to the altered metabolic state (enhanced glycolysis) of these cells. 3) The laboratory of Dr. Eric Nestler showed that cocaine, a powerful stimulant, activates SIRT1 expression in the nucleus accumbens in the brain, which triggers altered gene expression and enhanced drug reward. Here, we propose to test the model that HIV and drugs of abuse synergistically accelerate immune aging by reprogramming the transcriptional and metabolic profiles of T cells. We will test this model in a new in vitro system of T-cell senescence by adding drugs of abuse (stimulants, opiates) with and without HIV Tat to senescing T cells. We will also develop new technologies to measure key markers of immune activation and metabolism in primary T cells isolated from patients. Special emphasis lies on SIRT1 and posttranslational modifications of downstream transcription factors NF-kappaB, FoxO3A and HIF-1alpha. We expect that our studies will transform our understanding of immune aging in HIV-infected drug users by establishing novel links between HIV, abused substances and biological pathways of aging with direct therapeutic impact.