The Role of HIV Tat-induced SOCS3 in HIV Associated Dementia

描述(由申请人提供)： HIV相关性痴呆(HAD)是HIV感染引起的一种令人震惊的神经系统后果。虽然其原因尚不清楚，但人们认为HIV在中枢神经系统(CMS)免疫细胞内的复制导致其功能障碍，间接导致神经元死亡。虽然干扰素(干扰素)(3)是大脑中先天免疫反应的一种细胞因子介质，已被证明在防止艾滋病毒复制方面有效，但效果是短暂的。艾滋病毒最终能够克服其抗病毒作用并恢复复制，这一事件预示着HAD的进展。因此，关键是要确定艾滋病毒逃避这种保护性免疫反应的机制。最近，包括HIV在内的许多病毒和细菌病原体被证明可以诱导一系列细胞因子功能的负调控因子的表达，这些调节因子是细胞因子信号转导(SOCs)的抑制因子。这项建议的目的是确定在HIV感染的大脑中SOCS蛋白的表达是否介导了干扰素(3‘端S)的丧失，从而抑制艾滋病毒的复制，从而促进HAD的进展。首先，必须确定在感染艾滋病毒的大脑中是否存在SoCs的表达。这将通过评估死后HAD脑组织中SOCS蛋白的表达来在体内进行检验。此外，人类和小鼠中枢神经系统相关原代细胞的HIV TAT处理将被用于体外确定SOCs的诱导机制。其次，必须确定SoCS蛋白表达是否具有抑制干扰素(3)信号的功能，从而促进HIV在大脑中的复制。IFN0信号将在体外，在原代人类和小鼠细胞中，在STAT磷酸化、靶基因诱导和抑制HIV复制的水平上进行检测。将评估SOCS蛋白过表达和缺失的影响，以确定SOCS的表达是否足以介导干扰素(3‘S)的抗病毒反应抑制。这些研究将为HIV逃避中枢神经系统固有免疫系统的机制提供新的见解。公共卫生相关性：这项工作试图确定HIV在大脑中的复制，从而进展为HIV相关性痴呆(HAD)，是否受到细胞因子信号转导(SOCS)蛋白抑制物的帮助。确定这些蛋白质使艾滋病毒逃避大脑保护性免疫反应的潜在机制，将允许开发出加强这种防御的治疗方法。

DESCRIPTION (provided by applicant): HIV Associated Dementia (HAD) is a strikingly debilitating neurological consequence of HIV infection. Although its cause is still unclear, it is thought that HIV replication within immune cells of the Central Nervous System (CMS) results in their dysfunction, leading indirectly to neuronal death. While Interferon (IFN) (3, a cytokine mediator of the innate immune response in the brain, has been shown to be effective at preventing HIV replication, the effect is transient. HIV is eventually able to overcome its antiviral effects and resume replication, an event which heralds progression to HAD. Therefore, it is critical that the mechanism by which HIV evades this protective immune response be determined. Recently, numerous viral and bacterial pathogens, including HIV, have been shown to induce the expression of a family of negative regulators of cytokine function, the Suppressors Of Cytokine Signaling (SOCS). The goal of this proposal is to determine whether SOCS protein expression in the HIV-infected brain mediates the loss of IFN(3's ability to suppress HIV replication, and therefore promotes progression to HAD. First, it must be determined whether SOCS expression occurs in the HIV-infected brain. This will be examined in vivo by evaluation of SOCS protein expression in post-mortem HAD brain tissue. In addition, HIV Tat-treatment of CNS-relevant primary human and murine cells will be used in vitro to determine the mechanism of SOCS induction. Second, it must be determined whether SOCS protein expression functions to inhibit IFN(3 signaling, and thereby promote HIV replication in the brain. IFN0 signaling will be examined in vitro, in primary human and murine cells, at the level of STAT phosphorylation, target gene induction, and inhibition of HIV replication. The effect of both SOCS protein overexpression and deficiency will be evaluated to determine whether SOCS expression is sufficient to mediate inhibition of IFN(3's antiviral response. These studies will provide novel insight into the mechanism by which HIV is able to evade the innate immune system in the CNS. PUBLIC HEALTH RELEVANCE: This work seeks to determine whether HIV replication in the brain, and therefore progression to HIV Associated Dementia (HAD), is aided by Suppressor Of Cytokine Signaling (SOCS) proteins. Defining the potential mechanism by which these proteins allows HIV to evade the brain's protective immune response will allow for the development of therapies to strengthen this defense.