Reversing Tissue Fibrosis to Improve Immune Reconstitution in HIV

描述(申请人提供)：HIV联合抗病毒疗法(CART)的目标是抑制病毒复制和恢复免疫功能。对于现代CART，这是可能的，但免疫重建(IR)往往是不完整的，即使在多年的治疗后，显著的免疫异常仍然存在。这些持续性免疫异常的潜在机制可能与系统免疫激活(IA)在接受治疗的患者中没有完全正常化有关。慢性IA对淋巴组织的解剖有不利影响，是治疗后HIV感染不完全IR的主要因素。慢性IA与多种炎性细胞因子的表达有关，包括在继发性LN和GALT的滤泡旁T细胞区(TZ)启动胶原沉积的转化生长因子-β。这种累积性、渐进性的TZ纤维化过程破坏了成纤维细胞网状网络(FRCN)，FRCN是由中空纤维组成的网状结构，构成了TZ的骨骼解剖结构。T细胞绝对需要与FRCN接触才能迁移，形成免疫反应，从FRCN获得生存所需的IL-7。FRCN的缺失与T细胞存活受损有关，尤其是幼稚和中央记忆(CM)表型。这至少部分解释了CART环境中不完全IR和持续性免疫异常的机制。我们在SIV感染的非人类灵长类动物模型中进行了两项先导性研究，以阻止和/或逆转TZ纤维化，使用转化生长因子-β抑制剂吡非尼酮。我们在我们的初步数据中显示了这种方法的成功，这为我们提议的在人类HIV感染中使用转化生长因子-β抑制剂的试点研究提供了理论基础，以确定是否有潜力恢复FRCN，从而改善免疫功能。我们将在50名HIV+患者中使用药物氯沙坦进行双盲安慰剂对照研究，氯沙坦是FDA批准的血管紧张素受体抑制剂(ARB)，在SMAD 2，3的磷酸化水平上抑制转化生长因子-β，动物和人类研究表明，它逆转了肺、肝脏和肾脏现有的纤维化。我们不会使用吡非尼酮，因为它没有在美国FDA批准，也不能从生产它的公司获得。然而，我们坚信，在概念验证试点试验中，氯沙坦是更合适的选择。抗胶原形成的作用机制与吡非尼酮相同，它是安全的，耐受性很好，有长期的安全记录。重要的是，与吡非尼酮不同的是，氯沙坦还抑制了刺激胶原生成的基质金属蛋白酶，并具有可能在更广泛的背景下发生的抗炎特性。它抑制内毒素诱导的炎症信号，这是微生物移位的重要组成部分，并降低肿瘤坏死因子(TNF)、IL-6和可溶性黏附分子的水平。我们的假设是，使用氯沙坦治疗将1)降低IA水平，表现为IL-6、TNF、ICAM-1的下降；2)逆转现有的纤维化；3)恢复LN结构；4)改善外周和淋巴CD4T细胞及其功能；5)安全和耐受性良好。

DESCRIPTION (provided by applicant): The goal of combination antiviral therapy (cART) for HIV is to suppress viral replication and restore immune function. This is possible with modern cART however immune reconstitution (IR) is often incomplete and significant immunologic abnormalities persist, even after years of therapy. The underlying mechanisms driving these persistent immune abnormalities are likely related to the fact that systemic immune activation (IA) does not fully normalize in treated patients. Chronic IA has a detrimental effect on the anatomy of lymphoid tissues and is a primary factor in the incomplete IR in treated HIV infection. Chronic IA is associated with expression of multiple inflammatory cytokines, including TGF-¿ that initiates a process of collagen deposition in the parafollicular T cell zone (TZ) of secondary LN and GALT. This cumulative, gradual process of TZ fibrosis destroys the fibroblastic reticular network (FRCn) which is a mesh of hollow fibers that form the skeletal anatomy of the TZ. T cells absolutely require contact with the FRCn for migration, formation of immune responses, gain access to IL-7 from the FRCn that is required for survival. Loss of the FRCn is associated with impaired T cell survival, especially of the naive and central memory (CM) phenotype. This explains, at least in part, the mechanism of incomplete IR and persistent immunologic abnormalities in the setting of cART. We have performed two pilot studies in a non-human primate model of SIV infection to stop and/or reverse TZ fibrosis using the TGF-¿ inhibitor pirfenidone. We show in our preliminary data success with this approach which provides the rationale for our proposed pilot study of a TGF-¿ inhibitor in human HIV infection to determine if there is potential to restore the FRCn and thus improve immune function. We will perform a double-blind placebo controlled study in 50 HIV+ people on cART using the drug losartan, an FDA approved angiotensin receptor inhibitor (ARB) that inhibits TGF-¿ at the level of phosphorylation of SMAD 2,3 and animal and human studies show it reverses existing fibrosis in lung, liver, and kidney. We will not use pirfenidone because it is not FDA approved in the U.S. and is unavailable from the company that makes it. However, we strongly believe losartan is a more suitable choice in a proof of concept pilot trial. The mechanism of action against collagen formation is the same as pirfenidone and it is safe and well tolerated with a long and established safety record. Importantly, and in distinction to pirfenidone, losartan also inhibits matrix metalloproteases that stimulate collagen production and has anti-inflammatory properties that may IA in a broader context. It inhibits LPS-induced inflammatory signaling, an important component of microbial translocation, and decreases levels of tumor necrosis factor (TNF), IL-6, and soluble adhesion molecules. Our hypothesis is that treatment with the losartan will 1) decrease levels of IA as shown by a decrease in IL-6, TNF, ICAM-1; 2) reverse existing fibrosis; 3) restore LN architecture, 4) improve peripheral and lymphatic CD4 T cells and their function; and 5) be safe and well tolerated.