Limiting HIV establishment and maintenace by preserving intestinal immunity

尽管高效抗逆转录病毒疗法(ART)的发展有效地抑制了病毒的复制 在大多数艾滋病毒感染者中，仍然没有能够治愈这种感染的治疗方法。 接受抗逆转录病毒治疗的艾滋病毒感染者的残留疾病主要包括：(I)持续性炎症，有限的 CD4+T细胞的重建和过早的免疫衰老，以及(Ii)持久性储存库的存在 潜伏感染的细胞不受ART的影响，并负责病毒的快速反弹 如果ART被中断，则复制。Gut是艾滋病毒感染和复制发生的第一个主要地点， 表达共受体CCR5的CD4+T细胞与异源二聚体胃肠组织(GIT)归巢 以分子α4β7整合素为主要靶点。事实上，艾滋病毒感染与严重的 粘膜免疫和生理完整性，这被认为是艾滋病毒期间炎症的关键原因 感染。重要的是，炎症可能通过几种机制对艾滋病毒的持久性起到关键作用： 对易感细胞的感染，维持了宿主的持久性；上调了 共抑制受体，这有助于潜伏感染细胞的持久性；并限制 可能清除病毒的HIV特异性免疫反应。因此，制定战略的目的是 限制炎症和改善免疫反应，特别是在肠道和其他淋巴组织中可能 对艾滋病毒持久性产生重大影响，是艾滋病毒研究的一个关键优先事项。这件事的首要目标是 该项目旨在探索一种新型的联合白介素21和抗α4β7的治疗潜力 对经抗逆转录病毒治疗的感染SIV的恒河猴(RMS)的干预。基于一组令人兴奋的数据，我们 最近在单独使用IL-21或抗α4B7干预的单独研究中产生的，我们认为IL-21 21补充抗α4β7治疗将减少免疫功能障碍和炎症 (通过IL-21)以及保护肠道免受SIV感染和病毒学控制(通过抗α4β7)。AS 因此，我们假设，通过针对艾滋病毒持久性的关键贡献者，IL-21补充抗α4β7 治疗将在逐步减少和潜在消除艾滋病毒方面产生强大的协同效应 水库。 我们相信，拟议的研究将提供体内证据，证明机构减少(目标1)和 在IL-21和抗α4β7联合治疗后维持病毒库(目标2)。这项研究将是 在HIV感染的最相关的临床前动物模型中进行，并使用两个分子，作为一种 单一药物，正在进行癌症测试(IL-21)或被FDA批准用于治疗IBD和结肠炎(抗炎 α4β7)。此外，我们正在提出一系列机制研究，旨在定义分子和细胞 拟议干预措施的影响。如果成功，拟议的基于免疫的干预将通知 旨在从功能上治愈艾滋病毒感染的人体临床试验。因此，我们相信拟议的研究是 对HIV治愈研究领域具有重要而现实的意义。

Despite the development of potent anti-retroviral therapy (ART) that effectively suppresses virus replication in the majority of HIV-infected individuals, a treatment capable of curing this infection is still not available. Residual disease in ART-treated, HIV-infected individuals consists mainly of (i) persistent inflammation, limited CD4+ T cell reconstitution, and premature immune senescence, and (ii) the presence of persistent reservoirs of latently infected cells that are not affected by ART and are responsible for the rapid rebound of virus replication if ART is interrupted. Gut is the first major site where HIV infection and replication takes place, with CD4+ T cells that express the co-receptor CCR5 and the heterodimeric gastrointestinal tissue (GIT) homing molecule α4β7 integrin serving as the major target. Indeed, HIV infection is associated with a profound loss of mucosal immunological and physical integrity, which is considered a key cause of inflammation during HIV infection. Importantly, inflammation may critically contribute to HIV persistence by several mechanisms: driving the infection of susceptible cells that sustain the persistence of the reservoir; up-regulating the expression of co-inhibitory receptors, which contribute to the persistence of latently infected cells; and limiting the function of HIV-specific immune responses that could potentially clear the virus. Therefore, developing strategies aimed at limiting inflammation and improving immune responses especially in the gut and other lymphoid tissues may critically impact on HIV persistence, and is a key priority for HIV research. The overarching goal of this project is to explore the therapeutic potential of a novel, combined Interleukin (IL)-21 and anti-α4β7 intervention in ART-treated, SIV-infected rhesus macaques (RMs). Based on an exciting set of data we recently generated in separate studies that utilized IL-21 or anti-α4B7 interventions alone, we propose that IL- 21 supplementation of anti-α4β7 treatment will result in reduced immune dysfunction and inflammation (via IL-21) as well as in protection of gut from SIV infection and virologic control (via anti-α4β7). As such, we hypothesize that by targeting key contributors of HIV persistence, IL-21 supplementation of anti-α4β7 treatment will have a strong synergistic effect in the progressive reduction and potential elimination of the HIV reservoir. We are confident the proposed studies will provide in vivo evidence of reduced establishment (Aim 1) and maintenance (Aim 2) of the viral reservoir following combined IL-21 and anti-α4β7 treatment. This study will be conducted in the most relevant preclinical animal model of HIV infection and using two molecules that, as a single agent, are being tested for cancer (IL-21) or approved by the FDA for treatment of IBD and colitis (anti- α4β7). Moreover, we are proposing a series of mechanistic studies aimed at defining the molecular and cellular effects of the proposed intervention. If successful, the proposed immune-based intervention would inform human clinical trials aimed at functionally curing HIV infection. Thus, we believe that the proposed studies are of high and immediate significance to the field of HIV cure research.