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

项目总结 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 仍然是一个主要的公共卫生负担。目前的治疗方案通常能完全抑制病毒。 但需要终生坚持，因为病毒在以下情况下迅速从组织和细胞储存库反弹 治疗中断。此外，慢性炎症持续存在于CART抑制的个体和 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 重点关注导致持续病毒控制或消除病毒库的方法(无论是 “功能性”或“消毒”疗法)，另一个目标是开发减少顽固性 炎症过程使CART治疗期间的无病缓解复杂化。 最近的研究强调了胃肠道在艾滋病毒持久性中的关键作用，胃肠道 在CART期间，由体内绝大多数病毒库组成的区域。重要的是，残留的系统性 在感染艾滋病毒的人中观察到炎症，CART抑制的人似乎是由胃肠道增加引起的 渗透性。大量研究表明，肿瘤坏死因子α在维持亲和力方面发挥着关键作用。 与其他胃肠道疾病一起发生的炎症循环，如炎症性肠病。值得注意的是，肿瘤坏死因子α 已被证明有助于促进在艾滋病毒感染者中升高的促炎环境，但 肿瘤坏死因子α在HIV疾病期间胃肠道相关病理中的作用尚不清楚。我们假设 胃肠道上皮屏障的持续性损害是局部和全身残留的主要原因 HIV感染者在CART上的炎症，这在病毒库中起着重要作用 在胃肠道内持续存在，并减弱胃肠道，以及全身炎症会导致 恢复肠道功能，免疫动态平衡，减少贮藏者的持久性。 因此，肿瘤坏死因子α是一个有吸引力的靶点，用于缓解慢性肝炎期间的炎症环境 艾滋病毒感染阶段。因此，在非人类灵长类动物中，将使用两种不同的方法来靶向肿瘤坏死因子α。 艾滋病毒感染模型，i)FDA批准的抗肿瘤坏死因子α疗法的抗体(阿达利单抗、胡米拉)和ii)a 新的下游激酶小分子抑制剂RIPK1。胃肠道的范围和特点 病理与免疫稳态的恢复(目标1)及其数量、分布和特征 将在整个治疗过程中和在以下情况下对胃肠道内的病毒储存库(目标2)进行评估 实验结论。发现肿瘤坏死因子α在调节艾滋病毒胃肠道表现中的关键作用 将对未来艾滋病毒研究和治疗的方向产生重大影响。此外，使用任何一种 目前正在临床开发的一种新的抑制剂，或将FDA批准的药物重新用于新的用途 艾滋病毒感染的治疗方式是在寻找治愈方法方面的一项显着创新。

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.