Combined cytokine therapy for sustained HIV remission

联合细胞因子疗法可持续缓解艾滋病毒

• 批准号: 10573329
• 负责人: Rama Rao Amara
• 金额: $ 102.14万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-03-17 至 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10573329
• 关键词: Address; Adjuvant; Animal Euthanasia; Antiviral Response; B-Lymphocytes; BLR1 gene; Blood; CD4 Positive T Lymphocytes; CD8-Positive T-Lymphocytes; Cell physiology; Cells; Chronic; Clinic; Combined Modality Therapy; Complex; DNA; DNA/MVA vaccine; Data; Disease remission; Goals; HIV; HIV Infections; HIV/AIDS; Helper-Inducer T-Lymphocyte; Homing; Human; Immune; Immunity; Immunotherapeutic agent; In Vitro; Infection; Interferon Type II; Interleukin-12; Interleukin-15; Interleukin-2; Interruption; Knowledge; Lymphoid; Lymphoid Tissue; Macaca; Macaca mulatta; Modeling; Morbidity - disease rate; Natural Killer Cells; Plasma; Production; Proliferating; RNA; Role; SIV; SIV Vaccines; Safety; Structure of germinal center of lymph node; T cell response; T-Lymphocyte; T-Lymphocyte Subsets; TNF gene; TNFSF5 gene; Testing; Therapeutic; Tissues; Translating; Vaccinated; Vaccination; Vaccine Therapy; Viral; Viral reservoir; Viremia; Virus Replication; Work; antiretroviral therapy; antiviral immunity; chemokine receptor; cytokine; cytokine therapy; cytotoxic; improved; in vivo; mortality; novel; novel therapeutics; response; restoration; safety testing; secondary lymphoid organ; simian human immunodeficiency virus

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.

抽象的 该提案的总体目标是评估细胞因子疗法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，从而导致抗逆转录病毒治疗后病毒持续缓解 (ART) 使用 SIV/恒河猴 (RM) 模型阻断 HIV。抗 HIV 免疫功能失调和 病毒储存库的持续存在是实现持续病毒缓解必须解决的两个主要障碍 缺乏艺术。 ART在控制病毒复制方面非常有效，但并不能显着改善T细胞 发挥作用并减少病毒储存库。很明显，抗病毒 CD8 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，并且 ART 期间病毒库的很大一部分被浓缩 存在于 B 细胞滤泡和生发中心 (GC) 中的滤泡辅助 T 细胞 (Tfh) 中。然而，B 细胞滤泡 在慢性 HIV/SIV 感染期间，很大程度上缺乏抗病毒 CD8 T 细胞和 NK 细胞。因此，新疗法 恢复/增强抗病毒 CD8 T 细胞和 NK 细胞的功能，并促进这些细胞的滤泡归巢 显着增强淋巴组织内病毒库的清除，从而有助于持续的病毒缓解 分析 ART 中断 (ATI) 后。我们的初步数据表明，IL-12 加 IL-15/IL- 15Ra 治疗显着增强了 SIV 特异性 CD8+ T 的强度、细胞因子的产生和细胞毒性潜力 NK 细胞在体外明显优于任一细胞因子治疗。此外，联合细胞因子治疗 慢性 SHIV 感染是安全的，并导致抗病毒 CD8 T 细胞和 NK 细胞随滤泡归巢而扩增 与病毒控制相关的潜力。有趣的是，联合细胞因子疗法与 IL-15 单一疗法不同， 在体外和体内均不诱导CD4 T细胞增殖。鉴于这些非常令人鼓舞的结果，我们在此建议 全面测试 IL-15 和 IL-12 单独或组合对不同 T 和 NK 细胞亚群的影响 在慢性 SIV 感染和 ART 期间（目标 1），并研究这些变化如何影响 ART 下的病毒库 ART 中断后的病毒控制（目标 2）。此外，我们将最佳的细胞因子治疗与疫苗接种结合起来 进一步增强 SIV 特异性 CD4 和 CD8 T 细胞反应的程度和广度，我们希望这将进一步 提高治疗效果（目标 3）。这些研究将增进我们对 IL-15 和 IL-12 细胞因子如何发挥作用的了解 在慢性 SIV 感染和 ART 期间，不同亚群的 T 细胞和 NK 细胞的功能有不同的影响，以及什么 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。