Targeting SIV reservoirs with type I Interferons

使用 I 型干扰素靶向 SIV 病毒库

基本信息

批准号：
8930061
负责人：
Guido Silvestri
金额：
$ 23.49万
依托单位：
EMORY UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-09-19 至 2017-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8930061
关键词：
Acquired Immunodeficiency Syndrome Adherence Aftercare Anatomy Animal Model Animals Anti-Retroviral Agents Antiviral Agents Applications Grants Autopsy Biological Assay Blood Bone Marrow Brain Cell Separation Cells Clinical Clinical Trials Clinical assessments Colon DNA Development Disease Dose Drug toxicity Exhibits Gastrointestinal tract structure HIV HIV Infections Health Highly Active Antiretroviral Therapy Human Immune In Situ Hybridization Individual Infection Inflammation Interferon Type I Interferons Interruption Intervention Kidney Life Liver Location Lymph Node by Anatomic Site Macaca mulatta Measurement Measures Mediating Modeling Molecular Monitor Morbidity - disease rate Mucous Membrane Organ Pathway interactions Pharmaceutical Preparations Phase Pilot Projects Plasma Primates Protocols documentation Public Health RNA Reagent Regimen Research Research Personnel Residual state Reverse Transcriptase Polymerase Chain Reaction Risk Role SIV Safety Source Spleen System T-Lymphocyte Subsets Testing Therapeutic Time Viral Viral Load result Viremia Virus Virus Replication Work animal resource antiretroviral therapy base cell type cohort cost immune activation in vivo in vivo Model insight jejunum lymph nodes macrophage memory CD4 T lymphocyte mortality nonhuman primate novel novel strategies novel therapeutics pre-clinical receptor reconstitution research study

项目摘要

DESCRIPTION: Despite many major advances in AIDS research, including the development of anti-retroviral drugs that suppress virus replication and greatly reduce the mortality and morbidity of HIV infection, a treatment that can cure the infection is still not available. Indeed, combination antiretroviral therapy (ART) must be taken for life, thus posing significant challenges in terms of costs and clinical safety, and interruption of therapy results in a rapid rebound of viremia in the majority of HIV-infected individuals. To this end, new approaches are required to eradicate the reservoirs of latently infected cells that persist during ART and are the source of virus reactivation when therapy is interrupted. The overarching Aim of this proposal is to explore the therapeutic potential of type I interferon (IFN-I), that activates a very potent natural antiviral molecular system, in reducing the reservoirs of virus-infected cells that persist under ART. In the R21 phase of this grant application we propose to use the existing, well-established nonhuman primate model of SIVmac infection of rhesus macaques (RMs) to evaluate, in a relatively small pilot study, the potential impact of pegylated IFN-α2a (pIFN-α2a) on the overall size, anatomic location, and cellular distribution of the reservoirs of latently infected cells in ART-treated, SIV-infected RMs. We will use this very robust model to investigate directly in vivo and in multiple organs (i.e., blood, lymph nodes, spleen, mucosal tissues, etc.) and cell types (i.e., memory CD4+ T cell subsets and macrophages) whether and to what extent pIFN-α2a administration enhances the effect of ART on the virus reservoir. The results of the studies proposed in the R21 part of this application will pave the way for further experiments, to be conducted in the R33 phase of this proposal, in which we will test, in a larger cohort of SIV-infected RMs treated with long-term ART and exhibiting full suppression of virus replication, the effect of two consecutive cycles of pIFN-α2a treatment on (i) the size of the persisting reservoirs of latently infected cells, and (ii) the time of rebound of plasma viremia afer ART interruption. We believe that the proposed studies will provide unprecedented insights into the role of type I interferon in reducing and/or altering the cellular and anatomic distribution of the persistent virus reservoirs of latently infected cells in an in vivo model of pathogenic lentivral infection in which active virus replication is fully suppressed by ART. We believe that these results will be crucial to determine the potential of IFN-I therapy in HIV-infected individuals.

描述：尽管艾滋病研究取得了许多重大进展，包括开发出抑制病毒复制并大大降低艾滋病毒感染死亡率和发病率的抗逆转录病毒药物，但实际上仍然没有一种可以治愈这种感染的治疗方法。联合抗逆转录病毒治疗（ART）必须终生服用，因此在费用和临床安全性方面提出了重大挑战，并且治疗的中断会导致大多数艾滋病毒感染者的病毒血症迅速反弹。为此，需要新的方法。需要根除 ART 期间持续存在的潜伏感染细胞库，并且是该提案的总体目标是探索 I 型干扰素 (IFN-I) 的治疗潜力，该干扰素可激活非常有效的天然抗病毒分子系统，从而减少病毒感染细胞的储存量。坚持下去在 ART 的 R21 阶段，我们建议使用现有的、完善的恒河猴 (RM) SIVmac 感染模型来评估，在一项相对较小的试点研究中，聚乙二醇化 IFN-α 的潜在影响。 α2a (pIFN-α2a) 我们将使用这个非常强大的模型直接研究体内和多个器官（即血液、淋巴）中潜伏感染细胞库的总体大小、解剖位置和细胞分布。器官淋巴结、脾脏、粘膜组织等）和细胞类型（即记忆 CD4+ T 细胞亚群和巨噬细胞）pIFN-α2a 给药是否增强效果以及增强效果的程度本申请的 R21 部分中提出的研究结果将为在本提案的 R33 阶段进行的进一步实验铺平道路，我们将在更大的队列中进行测试。接受长期 ART 治疗并表现出病毒复制完全抑制的 SIV 感染 RM，连续两个周期的 pIFN-α2a 治疗对 (i) 潜伏感染细胞持续储存库的大小，以及 (ii) 的影响我们相信，所提出的研究将为 I 型干扰素在减少和/或改变病毒的细胞和解剖分布中的作用提供前所未有的见解。在致病性慢病毒感染的体内模型中，潜伏感染细胞的持久病毒库，其中活性病毒复制被 ART 完全抑制，我们相信这些结果对于确定 IFN-I 治疗 HIV 感染者的潜力至关重要。。

项目成果

期刊论文数量（1）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Despite early antiretroviral therapy effector memory and follicular helper CD4 T cells are major reservoirs in visceral lymphoid tissues of SIV-infected macaques.

尽管进行了早期抗逆转录病毒治疗，效应记忆和滤泡辅助 CD4 T 细胞仍然是感染 SIV 的猕猴内脏淋巴组织中的主要储存库。

DOI：
发表时间：
2020-01
期刊：
影响因子：
8
作者：
Rabezanahary, Henintsoa;Moukambi, Félicien;Palesch, David;Clain, Julien;Racine, Gina;Andreani, Guadalupe;Benmadid;Zghidi;Soundaramourty, Calayselvy;Tremblay, Cécile;Silvestri, Guido;Estaquier, Jérôme
通讯作者：
Estaquier, Jérôme