Antifibrotic Therapy to Improve Immune reconstitution in HIV

描述（由申请人提供）：本提案的主要目的是研究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）的新方法。这一点很重要，因为很少有人通过目前的抗逆转录病毒治疗获得正常免疫力，高达20%的病毒完全抑制的人CD4+ T细胞计数很少或没有增加。即使在那些外周血中CD4+ T细胞计数部分正常化的患者中，淋巴组织（LT）仍然消耗高达50%。这一观察结果可以解释接受抗逆转录病毒治疗的患者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粘膜病原体（如人乳头瘤病毒和单纯疱疹病毒）控制不佳。此外，在接受抗逆转录病毒药物治疗的艾滋病毒阳性患者中，结肠癌或肺癌和非艾滋病相关淋巴瘤引起的非艾滋病相关癌症死亡发生率不断上升，这突出表明需要辅助治疗来改善免疫功能。最近，我们描述了HIV感染者淋巴组织中的纤维化过程，该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，这对抗原呈递和T细胞稳态很重要。TZ纤维化的程度与ART开始时淋巴组织CD4+ T细胞群的大小和外周血CD4+ T细胞重构的程度有间接且显著的相关性。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，使用吡非尼酮（一种用于治疗特发性肺纤维化的药物）进行抗纤维化治疗，可以限制TZ中胶原蛋白的形成，并增强CD4 T细胞群的保存。我们假设，旨在限制或逆转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CD4+ T细胞数量和功能的显著增加。在这项提议中，我们将使用我们开发的SIV诱导淋巴纤维化的非人灵长类动物模型来确定抗纤维化治疗作为ART的辅助治疗是否可以逆转现有的纤维化并改善免疫重建。我们将在感染后12周使用吡非尼酮进行干预，无论是否使用抗逆转录病毒治疗，这一时间接近人类慢性感染，此时将考虑使用抗逆转录病毒治疗。我们将测量LT中胶原蛋白水平的变化，外周血和淋巴结中CD4+ T细胞群的变化，以及对抗原的原发性和回忆性免疫反应的功能评估。我们期望发现，与单独使用抗逆转录病毒治疗相比，吡非尼酮联合抗逆转录病毒治疗将显著增加CD4+ T细胞数量，并改善免疫功能。

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. PUBLIC HEALTH RELEVANCE: This project will evaluate therapies for HIV infection that may improve the ability of currently available anti-retroviral therapy to improve immune function. We will test a novel strategy to restore normal anatomy to lymph nodes that might allow more normal sized populations of CD4+ T cells to reconstitute. This has relevance to public health as HIV infection is a significant cause of morbidity and mortality world-wide and current therapies do not fully restore immune function.