Targeting the IL-10 pathway for an HIV Cure

 描述（由申请人提供）：虽然最近ART的优化已经预防了艾滋病并降低了大多数HIV感染者的艾滋病相关发病率和死亡率，但仍然没有可治愈HIV感染的可扩展治疗方法。因此，终身给予ART是必要的，在成本和临床安全性方面提出了重大挑战。治疗HIV感染的主要障碍包括：（1）持续的免疫异常，包括炎症，有限的CD 4 T细胞重建，以及抗病毒T细胞的功能衰竭。 单元格;（ii）低水平的病毒复制，特别是在组织中，和（iii）存在不受ART影响的长寿命潜伏感染细胞的萨尔库。重要的是，这些贡献者可能相互触发和维持，从而产生在ART期间维持HIV持续存在的恶性循环。改善抗病毒反应和减少受感染细胞的存活是治愈HIV所需要的。在这个提议中，使用完善的SIV感染的非人灵长类动物模型，我们将探索白细胞介素（IL）-10阻断对ART处理的SIV感染的恒河猴（RM）中的病毒持久性的影响。在初步工作中，我们已经表明IL-10是HIV持续存在的关键因素，其通过增加感染细胞和活化细胞的存活从而有利于病毒传播，增加免疫检查点阻断剂（IC B）的表达，已知其触发T细胞静止和病毒潜伏期，并且使产生IL-10的B细胞接近Tfh细胞（主要HIV储库）。基于这些初步结果，我们提出，给予抗IL-10阻断抗体（αIL-10）将通过以下方式降低HIV持续性：（i）降低可接种HIV储库的感染细胞的存活率，（ii）降低已知为T细胞静止和HIV潜伏期上游调节因子的分子的表达。在本项目的R21阶段，我们将对SIV感染的cART治疗RM给予αIL-10，并通过治疗对Tfh生存、生殖中心组织和ICB表达的影响进行监测，确定安全有效的剂量。在R33阶段，一旦确定了这种干预的安全性和最佳剂量，我们将提供IL-10中和对老年中心组织、Tfh存活率和HIV储库大小的积极影响的机制见解。如果我们的假设是正确的，我们预计在ART处理的SIV感染的RM中给予αIL-10，感染和活化细胞的存活率将降低，尤其是Tfh细胞。同时，持续性SIV储库将逐渐减少。总之，拟议的工作将通过在最相关的动物模型中对一种新干预措施进行严格控制的体内研究，提高对艾滋病毒潜伏期的理解。如果成功地诱导SIV储库的逐步减少，则所提出的治疗方法最终将在旨在治愈HIV感染的临床试验中进行测试。

 DESCRIPTION (provided by applicant): While the recent optimization of ART has prevented AIDS and reduced AIDS-related morbidities and mortality for the majority of HIV-infected individuals, a scalable treatment that can cure HIV infection is still not available. Thus, lifelon administration of ART is necessary, posing significant challenges in terms of costs and clinical safety. Major obstacles to curing HIV infection include (1) persistent immune abnormalities, including inflammation, limited CD4 T cell reconstitution, and functional exhaustion of antiviral T cells; (ii) low levels of viral replication, particularly in tissues, and (iii) the presence of a sall pool of long-lived latently infected cells that are not affected by ART. Importantly, these contributors may be triggering and sustaining each other, thus creating a vicious cycle that maintains HIV persistence during ART. As such, novel approaches aimed at limiting residual inflammation, improving antiviral responses and reducing the survival of infected cells are needed for curing HIV. In this proposal, using the well-established nonhuman primate model of SIV infection, we will explore the effects of Interleukin (IL)-10 blockade on virus persistence in ART-treated, SIV- infected rhesus macaques (RMs). In preliminary work we have shown that IL-10 is a key contributor to HIV persistence by augmenting the survival of infected cells and of activated cells thereby favoring viral dissemination, increasing the expression of immune check point blockers (ICB), known to trigger T cell quiescence and viral latency, and having IL-10 producing B cells at the proximity of Tfh cells, major HIV reservoir. Based on these preliminary results, we propose that administration of an anti-IL-10 blocking antibody (αIL-10) will reduce HIV persistence by: (i) decreasing the survival of infected cells that can seed the HIV reservoir, and (ii) decreasing the expression of molecules known to be upstream regulators of T cell quiescence and HIV latency. In the R21 phase of this project we will administer αIL-10 to SIV infected cART treated RMs and define a dose that is safe and efficacious as monitored by the impact of the treatment on Tfh survival, germinal center organization, and the expression of ICB. In the R33 phase, once safety and optimal dose of this intervention are established, we will provide mechanistic insights into the positive impact of IL-10 neutralization on germinal center organization, Tfh survival and magnitude of the HIV reservoir. If our hypothesis is correct, we expect that by administration of αIL-10 in ART-treated, SIV-infected RMs, survival of infected and activated cells will be reduced, and more specifically for Tfh cells. Concomitantly, the persistent SIV reservoir will be progressively reduced. In summary, the proposed work will translate an improved understanding of HIV latency through rigorously controlled in vivo studies of a novel intervention in the most relevant animal model. If successful in inducing progressive reduction of the SIV reservoir, the proposed treatment would ultimately be tested in clinical trial aimed at curing HIV infection.