HIV-associated Astrocyte Senescence as a Contributor to NeuroAIDS

衰老和与年龄相关的合并症是神经系统疾病的主要风险因素。随着人口 这给公共卫生带来了巨大压力。在美国，有一群人特别危险， 是人类免疫缺陷病毒-1（HIV-1）感染者，因为现在一半以上的人口是50岁 年龄或更大。受感染的个体会出现过早衰老的迹象， 这些功能障碍统称为HIV相关的神经认知障碍（HAND）。手的坚持 一直令人不安，因为随着高效抗逆转录病毒疗法（HAART）的出现，病毒足以 抑制因此，HAND的可能贡献者包括HAART药物本身以及 隐藏在CNS中的gp 120病毒包膜蛋白的储库。由于年龄增长对HAND至关重要，因此 这可能是衰老和影响HAND病理的因素之间的相互作用。我们提出 一种与年龄相关的星形胶质细胞应激反应，称为细胞衰老， 药物和gp 120可能是HAND的贡献者。我们将检测衰老相关的DNA损伤 反应，端粒损伤和氧化应激途径激活这些刺激。以来 衰老伴随着称为衰老的促炎蛋白的分泌， 相关的分泌表型，我们还将确定衰老星形胶质细胞的贡献， 炎症对这些HIV相关刺激的反应。我们还将确定哪些信号机制 通过使用主要炎症中心的药理学抑制剂来促进分泌。神经元是 对神经胶质活化也敏感，它们对活化神经胶质的毒性也是另一种可能的HAND 贡献者。我们将研究HIV相关的衰老星形胶质细胞的分泌物是否能够引起 神经毒性和药理学抑制炎症是否可以减轻这种反应。我们的整体 目的是确定老化和HIV相关因素之间的相互作用，作为HAND的贡献者。 由于许多与年龄相关的病理与衰老细胞、星形胶质细胞和神经胶质细胞的积累相关， 对HAART药物和gp 120应答的衰老可能是HAND的主要贡献者， 这种反应作为一种潜在的治疗方法可能是公共卫生的布恩。

Aging and age related co-morbidities are major risk factors for neurological pathologies. As the population ages, this puts a major strain on public health. One population that is particularly at risk in the United States are human immunodeficiency virus-1 (HIV-1) infected individuals as more than half of the population is now 50 years of age or older. Infected individuals show signs of premature aging and are prone to neurological dysfunctions collectively known as HIV-associated neurocognitive disorders (HAND). The persistence of HAND has been troubling since with the advent of highly active antiretroviral therapy (HAART), the virus is sufficiently suppressed. Possible contributors to HAND therefore include the HAART drugs themselves as well as reservoirs of the gp120 viral envelope protein hidden in the CNS. Since advancing age is critical for HAND, it is likely that there is an interaction between aging and the factors that influence HAND pathology. We propose that an age associated stress response in astrocytes known as cellular senescence in response to HAART drugs and gp120 could be a contributor to HAND. We will examine the senescence-associated DNA damage response, telomere damage and oxidative stress pathways activated in response to these stimuli. Since senescence is accompanied by the secretion of pro-inflammatory proteins known as the senescence- associated secretory phenotype, we will also determine the contribution of senescent astrocytes to inflammation in response to these HIV-associated stimuli. We will also determine which signaling mechanisms contribute to the secretions by using pharmacological inhibitors of major inflammatory centers. Neurons are also sensitive to glial activation and their toxicity in response to activated glia are another possible HAND contributor. We will examine if secretions from HIV-associated senescent astrocyte are able to cause neurotoxicity and whether pharmacological inhibition of inflammation can mitigate this response. Our overall objective is to determine the interaction between aging and HIV-associated factors as a contributor to HAND. Since many age associated pathologies are associated with the accumulation of senescent cells, astrocyte senescence in response to HAART drugs and gp120 could be a major contributor to HAND and Inhibition of this response could be a public health boon as a potential therapy.