Combined cytokine therapy for sustained HIV remission

摘要 本提案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，导致抗逆转录病毒治疗后持续的病毒缓解 (ART)使用SIV/恒河猴（RM）模型对HIV进行阻断。抗艾滋病毒免疫功能失调， 病毒储库的持续存在代表了两个必须解决的主要障碍，以实现持续的病毒缓解， ART不存在时，ART在控制病毒复制方面非常有效，但不能显著改善T细胞 功能和减少病毒库。很明显，抗病毒CD 8 T细胞对于控制HIV/SIV复制至关重要。 同样，最近的研究强调了NK细胞在控制HIV/SIV感染中的作用。大多数艾滋病毒 复制发生在次级淋巴器官中，并且在ART期间集中了相当一部分病毒储库 存在于B细胞滤泡和生发中心（GC）的T滤泡辅助细胞（Tfh）中。然而，B细胞滤泡 在慢性HIV/SIV感染期间，基本上缺乏抗病毒CD 8 T细胞和NK细胞。因此， 恢复/增强抗病毒CD 8 T细胞和NK细胞的功能，并促进这些细胞的滤泡归巢， 显著增强淋巴组织内病毒储库清除，从而有助于持续的病毒缓解 分析性ART中断（ATI）后。我们的初步数据表明，IL-12加IL-15/IL-15的联合治疗可以显著降低IL-12和IL-15的表达。 15 Ra治疗显著增强SIV特异性CD 8 + T细胞的数量、细胞因子产生和细胞毒性潜力， NK细胞在体外显著上级任一细胞因子治疗。此外，在治疗期间， 慢性SHIV感染是安全的，并导致抗病毒CD 8 T细胞和NK细胞扩增，并有滤泡归巢 与病毒控制相关的潜力。有趣的是，与IL-15单一疗法不同， 在体外和体内均不诱导CD 4 T细胞增殖。鉴于这些非常令人鼓舞的结果，我们建议 全面测试IL-15和IL-12单独或联合对不同T和NK细胞亚群的作用 在慢性SIV感染和ART期间（目的1），并研究这些变化如何影响ART下的病毒库 以及ART中断后的病毒控制（目标2）。此外，我们将联合收割机将最佳细胞因子疗法与疫苗接种相结合 进一步增强SIV特异性CD 4和CD 8 T细胞应答的幅度和广度，我们希望这将进一步 改善治疗效果（目标3）。这些研究将进一步加深我们对IL-15和IL-12细胞因子 在慢性SIV感染和ART期间，不同的T细胞和NK细胞亚群的功能受到不同的影响， 由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.