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

描述（由申请人提供）： 艾滋病毒相关性痴呆（HAD）是艾滋病毒感染的一种显著衰弱的神经系统后果。虽然其原因尚不清楚，但据认为，中枢神经系统（CMS）免疫细胞内的HIV复制导致其功能障碍，间接导致神经元死亡。虽然干扰素（IFN）β，一种脑内先天免疫反应的细胞因子介导剂，已被证明能有效防止HIV复制，但这种作用是短暂的。HIV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，确定HIV逃避这种保护性免疫反应的机制至关重要。最近，许多病毒和细菌病原体，包括HIV，已经显示诱导细胞因子功能的负调节因子家族的表达，细胞因子信号转导抑制因子（SOCS）。本研究的目的是确定SOCS蛋白在HIV感染脑中的表达是否介导IFN β抑制HIV复制能力的丧失，从而促进HAD的进展。首先，必须确定SOCS表达是否发生在HIV感染的大脑中。这将通过评估死后HAD脑组织中SOCS蛋白表达来体内检查。此外，将在体外使用CNS相关原代人和鼠细胞的HIV Tat处理来确定SOCS诱导机制。其次，必须确定SOCS蛋白表达是否具有抑制IFN β信号传导的功能，从而促进HIV在脑中的复制。将在体外，在原代人和鼠细胞中，在STAT磷酸化、靶基因诱导和HIV复制抑制水平上检查IFN 0信号传导。将评估SOCS蛋白过度表达和缺乏的影响，以确定SOCS表达是否足以介导IFN β抗病毒应答的抑制。这些研究将为HIV逃避CNS先天免疫系统的机制提供新的见解。公共卫生相关性：这项工作旨在确定HIV在大脑中的复制，以及因此发展为HIV相关性痴呆（HAD）是否受到细胞因子信号转导抑制因子（SOCS）蛋白的帮助。确定这些蛋白质允许HIV逃避大脑保护性免疫反应的潜在机制将允许开发加强这种防御的疗法。

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.