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

描述：在HIV感染者中引入高效抗逆转录病毒疗法（HAART），将HIV感染从一种致命的疾病转变为一种可控制的疾病。然而，最近的证据表明，经HAART治疗成功的艾滋病毒感染者以更快的速度出现与年龄相关的病理，包括心血管疾病、神经退行性疾病和癌症。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）CD28记忆T细胞。类似的早衰综合征也发生在慢性阿片类和兴奋剂使用者身上，他们出现多系统退行性疾病并伴有免疫激活症状。我们寻求分子洞察连接HIV感染和药物滥用与慢性免疫激活的共享途径，以开发旨在减缓加速免疫衰老和增强HIV感染吸毒者健康寿命的新疗法。我们最近发现NAD+依赖的去乙酰化酶SIRT1是HIV感染中免疫激活的关键调节因子。SIRT1是酵母菌sir2酶的人类同源物，与酵母菌和蠕虫的寿命延长有关。SIRT1与HIV感染吸毒者免疫老化加速有关的证据有三个方面：1)我们发现SIRT1活性被HIV反激活子Tat抑制，这一过程导致下游SIRT1靶点（如感染T细胞中的免疫刺激转录因子NF-kappaB）乙酰化增强。2)在未发表的初步研究中，我们发现SIRT1蛋白在CD28-衰老记忆T细胞中表达缺失，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，可卡因这种强效兴奋剂可以激活大脑伏隔核中SIRT1的表达，从而引发基因表达的改变和药物奖励的增强。在这里，我们提出通过重新编程T细胞的转录和代谢谱来测试HIV和滥用药物协同加速免疫衰老的模型。我们将在一个新的体外T细胞衰老系统中测试这个模型，方法是向衰老的T细胞中加入带有或不带有HIV Tat的滥用药物（兴奋剂、鸦片剂）。我们还将开发新技术来测量从患者身上分离的原代T细胞中免疫激活和代谢的关键标志物。特别强调SIRT1和下游转录因子NF-kappaB、FoxO3A和HIF-1alpha的翻译后修饰。我们期望我们的研究将通过在艾滋病毒、滥用物质和衰老的生物学途径之间建立新的联系，从而改变我们对艾滋病毒感染吸毒者免疫衰老的理解，并具有直接的治疗影响。

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.