Antifibrotic Therapy to Improve Immune reconstitution in HIV

描述（由申请人提供）：该提案的主要目的是研究一种新的方法，以改善免疫重建（IR）时，抗逆转录病毒治疗（ART）开始在艾滋病毒感染者。这是重要的，因为很少有人能用目前的ART获得正常的免疫力，高达20%的完全病毒抑制的人CD4+ T细胞计数很少或没有增加。即使在外周血中CD4+ T细胞计数部分正常化的那些人中，淋巴组织（LT）仍然消耗多达50%。这一观察结果可以解释接受抗逆转录病毒治疗的人的免疫功能持续缺陷，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状瘤病毒和单纯疱疹病毒的控制不良。此外，在用ARV治疗的HIV+人群中，结肠癌或肺癌和非AIDS相关淋巴瘤引起的非AIDS相关癌症死亡的发生率增加，突出了对改善免疫功能的预防性治疗的需要。 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副皮质T细胞区（TZ）的关键结构，所述副皮质T细胞区对于抗原呈递和T细胞稳态是重要的。TZ变得纤维化的程度与淋巴组织中CD4+ T细胞群的大小和开始ART时外周血中CD4+ T细胞重建的程度间接且显著相关。在我们的初步数据中，我们在SIV感染的非人灵长类动物模型中证明，吡非尼酮（一种用于治疗特发性肺纤维化的药物）的抗纤维化治疗限制了TZ中的胶原蛋白形成并增强了CD4 T细胞群的保存。我们假设，旨在限制或逆转LT中病理性纤维化的治疗将恢复TZ的关键解剖要素，这反过来又会导致显著更大的CD4+ T细胞数量和功能。在该提案中，我们将使用我们已经开发的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的连续治疗给予的抗纤维化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周用吡非尼酮进行干预，联合或不联合ART，这是一个接近人类慢性感染的时间，此时将考虑ART。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，以及对抗原的初级和回忆反应的免疫功能评估。我们预期发现，与单独使用ART相比，ART与吡非尼酮联合使用将导致显著更大的CD4+ T细胞群和改善的免疫功能。

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.