Attenuating Inflammation to Restore GI Tract Integrity and Reduce Viral Reservoirs During cART

项目摘要 尽管联合抗逆转录病毒疗法（cART）取得了进展，但人类免疫缺陷病毒（HIV）感染仍是一个严重的问题。 仍然是一个重大的公共卫生负担。目前的治疗方案往往达到完全抑制病毒 但需要终身坚持，因为病毒在感染后很快从组织和细胞库反弹， 治疗中断。此外，慢性炎症在cART抑制的个体中持续存在， 即使在没有可检测到的病毒血症的情况下也会导致合并症。因此，艾滋病毒研究的一个主要目标是 专注于导致持续的病毒控制或消除病毒储存库的方法（无论是 "功能性"或"杀菌性"治疗），另外的目标是开发减少持久性 在cART治疗期间使无病缓解复杂化的炎症过程。 最近的工作强调了胃肠道在HIV持续存在中的关键作用，胃肠道 在cART期间，包含体内绝大多数病毒储库的管道。重要的是， 在HIV感染、cART抑制个体中观察到的炎症似乎是由胃肠道增加驱动的 磁导率大量的研究表明，TNF α在维持促凋亡中起着关键作用， 与其他胃肠道疾病（如炎症性肠病）一起发生的炎症周期。值得注意的是， 已显示有助于HIV感染个体中升高的促炎性环境，但 TNF α在HIV疾病期间GI相关病理学中的作用尚不清楚。我们假设 对胃肠道上皮屏障的持续性损伤是局部和全身性残留的主要原因。 在接受cART治疗的HIV感染者中，炎症在病毒储库中起重要作用 持续存在于胃肠道内，并减弱胃肠道和全身性炎症将导致 恢复肠道恢复、免疫稳态和降低储库持久性。 因此，TNF α是一个有吸引力的目标，以减轻炎症环境中的慢性 HIV感染的阶段。因此，将在非人灵长类动物中使用两种不同的靶向TNF α的方法 HIV感染模型，i）FDA批准的抗TNF α治疗抗体（阿达木单抗，修美乐）和ii）a 下游激酶RIPK1的新型小分子抑制剂。胃肠道的范围和特点 病理学和免疫稳态的恢复（目的1）和数量，分布和特征 将在整个治疗过程中和治疗后评价胃肠道内病毒储库的数量（目标2）。 实验的结论。发现TNF α在调节HIV胃肠道表现中的关键作用 这将对未来艾滋病研究和治疗的方向产生重大影响。此外，使用 一种目前正在临床开发的新型抑制剂，或将FDA批准的药物作为新的 HIV感染的治疗方式代表了寻求治愈的显著创新。

PROJECT SUMMARY Despite advances in combination antiretroviral therapy (cART), human immunodeficiency virus (HIV) infection remains a major public health burden. Current therapeutic regimens often achieve complete viral suppression but require lifelong adherence, as the virus quickly rebounds from tissue and cellular reservoirs following treatment interruption. Moreover, chronic inflammation persists in cART-suppressed individuals and contributes to comorbidities even in the absence of detectable viremia. Thus, a major goal in HIV research is focused on approaches that lead to either sustained viral control or elimination of viral reservoirs (either a `functional' or `sterilizing' cure), with the additional objective to develop approaches that reduce the persistent inflammatory process that complicates disease-free remission during cART treatment. Recent work has highlighted the critical role of the gastrointestinal (GI) tract in HIV persistence, with the GI tract comprising the vast majority of viral reservoirs in the body during cART. Importantly, residual systemic inflammation observed in HIV infected, cART suppressed individuals appears driven by increased GI tract permeability. A substantial body of research has shown a critical role for TNFα in perpetuating the pro- inflammatory cycle that occurs with other GI disorders, such as inflammatory bowel disease. Notably, TNFα has been shown to contribute to the pro-inflammatory milieu that is elevated in HIV infected individuals, but the role of TNFα in GI-associated pathology during HIV disease is not well understood. We hypothesize that persistent damage to the GI tract epithelial barrier is a major cause of residual local and systemic inflammation in HIV infected individuals on cART, which plays an important role in viral reservoir persistence within the GI tract, and attenuating GI tract, and systemic, inflammation will lead to restored gut restoration, immune homeostasis and reduced reservoir persistence. TNFα therefore represents an attractive target for mitigating the inflammatory milieu during the chronic phase of HIV infection. Thus, two different approaches to target TNFα will be utilized in a non-human primate model of HIV infection, i) an FDA-approved antibody against TNFα therapy (adalimumab, Humira) and ii) a novel small molecule inhibitor of the downstream kinase, RIPK1. The extent and characteristics of GI tract pathology and the restoration of immune homeostasis (Aim 1) and the quantity, distribution, and characteristics of the viral reservoir within the GI tract (Aim 2) will be evaluated throughout treatment and following the conclusion of the experiments. Discovering a critical role for TNFα in modulating the GI manifestations of HIV would have a significant impact on the direction of future HIV research and treatment. Moreover, use of either a novel inhibitor that is currently in clinical development, or the re-purposing of an FDA-approved drug, as new therapeutic modalities for HIV infection represent a marked innovation in the search for a cure.