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

描述：在艾滋病毒感染者中引入高效抗逆转录病毒疗法(HAART)将艾滋病毒感染从一种致命的情况转变为一种可控制的疾病。然而，最近的证据表明，成功接受HAART治疗的HIV感染患者会加速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的HIV感染患者也显示出持续免疫激活和加速免疫老化的迹象，在年轻时就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剂和兴奋剂使用者中，他们患有多系统退行性疾病，并伴有免疫激活的症状。我们寻求对将艾滋病毒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，以开发旨在减缓加速的免疫衰老并提高艾滋病毒感染吸毒者的健康寿命的新疗法。我们最近发现依赖NAD+的脱乙酰酶SIRT1是HIV感染中免疫激活的关键调节因子。SIRT1是酵母sir2酶的人类同源物，已被认为与酵母和蠕虫的寿命延长有关。将SIRT1与HIV感染的吸毒者加速免疫衰老联系起来的证据有三个：1)我们表明SIRT1的活性被HIV反式激活因子TAT抑制，这一过程导致受感染T细胞中SIRT1下游靶标的乙酰化增强，如免疫刺激转录因子NF-kappaB。2)在未发表的初步研究中，我们发现SIRT1蛋白在CD28衰老的记忆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)埃里克·内斯特勒博士的实验室表明，可卡因是一种强大的兴奋剂，它激活了大脑伏隔核中SIRT1的表达，从而触发了基因表达的变化，并增强了药物奖赏。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细胞的转录和代谢特征来协同加速免疫衰老的模型。我们将在一种新的体外T细胞衰老系统中测试这一模型，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)和不含HIV TAT的药物。我们还将开发新技术，以测量从患者分离的原始T细胞中免疫激活和代谢的关键标志。特别强调SIRT1和下游转录因子NF-kappaB、FOXO3a和HIF-1α的翻译后修饰。我们预计，我们的研究将通过在艾滋病毒、滥用物质和衰老的生物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，并产生直接的治疗影响。

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.