Combined cytokine therapy for sustained HIV remission

摘要 这项建议的总体目标是评估细胞因子治疗和疫苗接种的安全性和治疗潜力。 恢复/增强抗病毒免疫功能，使抗逆转录病毒治疗后病毒持续缓解 (ART)使用SIV/恒河猴(RM)模型中断抗艾滋病毒。抗艾滋病毒免疫功能障碍和 病毒库的持久性是实现病毒持续缓解必须解决的两大障碍 艺术的缺失。ART在控制病毒复制方面非常有效，但不能显著提高T细胞 发挥功能，减少病毒库。很明显，抗病毒的CD8T细胞对于控制HIV/SIV的复制至关重要。 同样，最近的研究强调了NK细胞在控制艾滋病毒/SIV感染中的作用。大多数HIV病毒 复制发生在次级淋巴器官中，在抗逆转录病毒治疗期间，相当一部分病毒库集中在一起 位于B细胞滤泡和生发中心(GC)的T滤泡辅助细胞(TFH)。然而，B细胞滤泡是 在慢性HIV/SIV感染期间，大部分缺乏抗病毒的CD8 T细胞和NK细胞。因此，新的治疗方法 恢复/增强抗病毒CD8 T细胞和NK细胞的功能，并促进这些细胞的卵泡归巢 显著增强淋巴组织内病毒库的清除，有助于病毒的持续缓解 在分析艺术中断(ATI)之后。我们的初步数据显示，IL-12和IL-15/IL-2的结合。 15Ra治疗显著增强SIV特异性CD8 T细胞的数量、细胞因子的产生和细胞毒活性 NK细胞在体外明显优于任一种细胞因子处理。此外，联合细胞因子治疗期间 慢性SHV感染是安全的，并导致抗病毒CD8 T细胞和NK细胞以滤泡归巢方式扩张 与病毒控制相关的潜力。有趣的是，与IL-15单一疗法不同，联合细胞因子疗法， 在体外和体内均不能诱导CD4T细胞增殖。鉴于这些非常令人鼓舞的结果，我们在这里建议 综合检测IL-15、IL-12单独或联合应用对不同T、NK细胞亚群的影响 在慢性SIV感染和ART(目标1)期间，并调查这些变化如何影响ART下的病毒库 和ART阻断后的病毒控制(目标2)。此外，我们将把最佳细胞因子疗法与疫苗接种结合起来。 为了进一步提高SIV特异性的CD4和CD8T细胞反应的幅度和广度，我们希望进一步 提高治疗效益(目标3)。这些研究将增进我们对IL-15和IL-12细胞因子如何 慢性SIV感染和抗逆转录病毒治疗对不同T和NK细胞亚群功能的不同影响 细胞因子治疗和疫苗接种诱导的免疫机制有助于控制慢性SIV/HIV感染。

Abstract The overall goal of this proposal is to evaluate the safety and therapeutic potential of cytokine therapy and vaccination to restore/enhance function of anti-viral immunity that will lead to sustained viral remission following anti-retroviral therapy (ART) interruption against HIV using the SIV/Rhesus macaque (RM) model. Dysfunctional anti-HIV immunity and persistence of viral reservoirs represent two major obstacles that must be addressed to achieve sustained viral remission in the absence of ART. ART is highly effective in controlling virus replication but does not significantly improve T cell function and reduce viral reservoirs. It is clear that anti-viral CD8 T cells are critical for the control of HIV/SIV replication. Similarly, recent studies have highlighted the role of NK cells in controlling HIV/SIV infections. The majority of HIV replication occurs in secondary lymphoid organs and a significant fraction of viral reservoirs during ART are concentrated in T follicular helper cells (Tfh) that reside in B cell follicles and germinal centers (GC). However, B cell follicles are largely devoid of anti-viral CD8 T cells and NK cells during chronic HIV/SIV infection. Thus, novel therapies that restore/enhance function of both anti-viral CD8 T cells and NK cells, and promote follicular homing of these cells will significantly enhance clearance of viral reservoirs within lymphoid tissues there by contribute to sustained viral remission following analytical ART interruption (ATI). Our preliminary data demonstrated that combination of IL-12 plus IL-15/IL- 15Ra treatment markedly enhances the magnitude, cytokine production and cytotoxic potential of SIV-specific CD8+ T and NK cells that was markedly superior to either cytokine treatment in vitro. In addition, combination cytokine treatment during chronic SHIV infection was safe and resulted in expansion of anti-viral CD8 T cells and NK cells with follicular homing potential that was associated with viral control. Interestingly, the combination cytokine therapy, unlike IL-15 monotherapy, did not induce proliferation of CD4 T cells both in vitro and in vivo. Given these highly encouraging results, here we propose to comprehensively test the effects of IL-15 and IL-12 either alone or in combination on different T and NK cell subsets during chronic SIV infection and ART (Aim 1), and investigate how these changes influence viral reservoirs under ART and viral control after ART interruption (Aim 2). In addition, we will combine the optimal cytokine therapy with vaccination to further enhance the magnitude and breadth of SIV-specific CD4 and CD8 T cell responses that we hope will further improve the therapeutic benefit (Aim 3). These studies will advance our knowledge about how IL-15 and IL-12 cytokines differentially influence the function of different subsets of T and NK cells during chronic SIV infection and ART, and what immune mechanisms induced by cytokine therapy and vaccination contribute to control of chronic SIV/HIV infections.