Antifibrotic Therapy to Improve Immune reconstitution in HIV

描述(由申请人提供)：这项建议的主要目标是研究一种新的方法，以在艾滋病毒感染者开始抗逆转录病毒治疗(ART)时改善免疫重建(IR)。这一点意义重大，因为在目前的抗逆转录病毒疗法中，很少有人获得正常免疫，而完全抑制病毒的患者中，高达20%的人的CD4+T细胞计数几乎或没有增加。即使在外周血中CD4+T细胞计数部分正常者，淋巴组织(LT)仍有高达50%的耗竭。这一观察结果可能解释了接受抗逆转录病毒治疗的人的免疫功能持续缺陷的原因，包括疫苗反应性差，细菌感染增加，以及对人乳头瘤病毒和单纯疱疹病毒等粘膜病原体控制不力。此外，在接受抗逆转录病毒治疗的HIV+患者中，结肠癌或肺癌以及非艾滋病相关淋巴瘤导致的非艾滋病相关癌症死亡的发病率不断上升，这突显了辅助治疗改善免疫功能的必要性。最近，我们描述了HIV感染者淋巴组织中的纤维化过程，破坏了次级淋巴组织的皮质旁T细胞区(TZ)的关键结构，这些结构对抗原递呈和T细胞动态平衡至关重要。TZ纤维化的程度与开始抗逆转录病毒治疗时淋巴组织中的CD4+T细胞群的大小和外周血中的CD4+T细胞重建的大小间接且显著相关。在我们的初步数据中，我们在SIV感染的非人类灵长类动物模型中证明了吡非尼酮的抗纤维化治疗，一种用于治疗特发性肺纤维化的药物，限制了TZ中胶原的形成，并加强了CD4T细胞群的保存。我们假设，针对限制或逆转LT病理性纤维化的治疗将恢复TZ的关键解剖要素，这反过来将导致显著更多的CD4+T细胞数量和功能。在这项建议中，我们将使用我们开发的SIV诱导的淋巴纤维化的非人灵长类动物模型来确定作为ART辅助治疗的抗纤维化治疗是否可以逆转现有的纤维化并促进免疫重建。我们将在感染后12周使用和不使用抗逆转录病毒治疗的吡非尼酮进行干预，这一时间接近于人类慢性感染，此时将考虑抗逆转录病毒治疗。我们将测量LT中胶原水平的变化，外周血和淋巴结中CD4+T细胞数量的变化，以及通过对抗原的初级和召回反应来评估免疫功能。我们预计，与单独使用ART相比，与吡非尼酮联合应用ART将导致显著更多的CD4+T细胞数量和免疫功能改善。

DESCRIPTION (provided by applicant): The primary objective for this proposal is to examine a novel approach to improve immune reconstitution (IR) when antiretroviral therapy (ART) is begun in HIV infected persons. This is significant because few individuals achieve normal immunity with current ART and up to 20% people with complete viral suppression have little or no increase in CD4+ T cell counts. Even among those with partial normalization of CD4+ T cell counts in peripheral blood, lymphoid tissues (LT) remain depleted by as much as 50%. This observation may explain persistent defects in immune function among people treated with antiretroviral therapy including poor vaccine responsiveness, increased bacterial infections, and poor control of mucosal pathogens like human papilloma virus and herpes simplex virus. Further, the increasing incidence of non-AIDS related cancer deaths from colon or lung cancer and non-AIDS associated lymphoma among HIV+ persons treated with ARV highlight the need for adjunctive therapies to improve immune function. Recently we described a process of fibrosis in lymphatic tissues of HIV infected persons that destroys critical structures of the paracortical T cell zone (TZ) of secondary lymphatic tissues important for antigen presentation and T cell homeostasis. The degree to which the TZ becomes fibrotic is indirectly and significantly correlated to the size of the CD4+ T cell population in lymphatic tissues and the magnitude of CD4+ T cell reconstitution in peripheral blood when ART is begun. In our preliminary data we demonstrate in a non-human primate model of SIV infection that antifibrotic therapy with pirfenidone, a drug used for the treatment of idiopathic pulmonary fibrosis, limits collagen formation in the TZ and enhances preservation of CD4 T cell populations. We hypothesize that therapies directed at limiting or reversing pathologic fibrosis in LT will restore critical anatomical elements of the TZ which, in turn, will lead to significantly greater CD4+ T cell numbers and function. In this proposal we will use the non-human primate model of SIV induced lymphatic fibrosis that we have developed to determine if antifibrotic therapy given as adjunctive therapy with ART can reverse existing fibrosis and improve immune reconstitution. We will intervene with pirfenidone, with and without ART, at 12 weeks post-infection, a time that approximates chronic infection in humans when ART would be considered. We will measure changes in levels of collagen in LT, changes in CD4+ T cell populations in peripheral blood and lymph node, and functional assessments of immunity with primary and recall responses to antigens. We anticipate finding that ART with pirfenidone will result in a significantly larger CD4+ T cell population and improved immune function than when ART is used alone.