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: 10348184
• 负责人: Rama Rao Amara
• 金额: $ 89.12万
• 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/10348184
• 关键词: AIDS/HIV problem; Address; Adjuvant; Animals; Anti-Infective Agents; 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 biosynthesis; DNA/MVA vaccine; Data; Disease remission; Goals; HIV; HIV Infections; 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; 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 抗病毒免疫的恢复/增强功能，这将导致抗逆转录病毒治疗后持续的病毒缓解 （ART）使用SIV/Rhesus Macaque（RM）模型对HIV的中断。功能失调的抗HIV免疫和 病毒库的持久性代表了必须解决的两个主要障碍，以实现持续的病毒缓解 缺乏艺术。艺术在控制病毒复制方面非常有效，但不能显着改善T细胞 功能并减少病毒库。显然，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机构中 在B细胞卵泡和生发中心（GC）中的T卵泡辅助细胞（TFH）中。但是，B细胞卵泡是 在慢性HIV/SIV感染期间，很大程度上没有抗病毒CD8 T细胞和NK细胞。因此，新颖的疗法 还原/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 通过持续的病毒缓解，显着增强了淋巴组织中病毒储存的清除 分析艺术中断（ATI）。我们的初步数据表明，IL-12加IL-15/IL-的组合 15RA治疗明显增强了SIV特异性CD8+ T和 NK细胞在体外明显优于任何一种细胞因子治疗。另外，在 慢性SHIV感染是安全的，导致抗病毒CD8 T细胞和NK细胞的膨胀 与病毒控制相关的潜力。有趣的是，与IL-15单一疗法不同，组合细胞因子疗法， 在体外和体内都不会诱导CD4 T细胞的增殖。考虑到这些极其令人鼓舞的结果，我们在这里提出 全面测试IL-15和IL-12对不同T和NK细胞子集的影响 在慢性SIV感染和艺术期间（AIM 1），并研究这些变化如何影响ART下的病毒储层 和艺术中断后的病毒控制（AIM 2）。此外，我们将将最佳细胞因子疗法与疫苗接种结合 为了进一步增强SIV特异性CD4和CD8 T细胞反应的大小和广度，我们希望能进一步 提高治疗益处（AIM 3）。这些研究将促进我们对IL-15和IL-12细胞因子的了解 在慢性SIV感染和ART期间差异影响T和NK细胞不同子集的功能，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。