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Combined cytokine therapy for sustained HIV remission

联合细胞因子疗法可持续缓解艾滋病毒

基本信息

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
项目类别：
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

项目摘要

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.

摘要