Targeting SIV reservoirs with type I Interferons

使用 I 型干扰素靶向 SIV 病毒库

• 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
• 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

 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，包括开发抑制病毒复制并大大降低HIV感染的死亡率和发病率的抗逆转录病毒药物，这种治疗仍无法治愈感染。的确， 终生必须采取抗逆转录病毒疗法（ART），从而在成本和临床安全方面占据重大挑战，而治疗的中断导致大多数HIV感染者的病毒血症迅速反弹。为此，需要采用新的方法来放射性的放射性储层，这些储层是在艺术期间持续存在的潜在感染细胞的 该提案的总体目的是探索I型干扰（IFN-I）的治疗潜力，该治疗潜力激活了非常潜在的天然抗病毒药物分子系统，以减少持续存在的病毒感染细胞的储层 在艺术下。在此赠款应用的R21阶段，我们建议使用现有的，良好的非人类私人模型SIVMAC猕猴感染（RMS）在一项相对较小的试点研究中评估Pegypated IFN-α2A（PIFN-α2A）的潜在影响。 在ART处理的SIV感染的RMS中，在整体大小，解剖位置和细胞分布。我们将使用这个非常健壮的模型在体内和多个器官（即血液，淋巴结，脾脏，粘膜组织等）和细胞类型（即记忆CD4+ T细胞子群和巨噬细胞）和细胞类型（是否以及对PIFN-α2A的何种程度上对Art的效果增强了pifn-21的效果，r 21）的效果21实验，在该提案的R33阶段进行，在其中，我们将在较大的SIV感染的RMS中进行测试，这些RMS经过长期艺术和实验对病毒复制的完全抑制，PIFN-α2A治疗的两个保守循环对（i）Plasseve reserve time time time time time time time time tirementire tirementime time aftermane tire and time a ii（II）的效果（ii）的效果（ii）均为II）。艺术中断。我们认为，拟议的研究将为I型干扰在减少和/或改变细胞和解剖学分布中的作用方面提供前所未有的见解。 在病原体感染的体内模型中，持续的病毒储量在其体内受感染模型中被ART完全抑制了活性病毒复制。我们认为，这些结果对于确定IFN-I治疗在HIV感染的个体中的潜力至关重要。

项目成果

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: 10.1038/s41385-019-0221-x
• 发表时间: 2020
• 期刊: Mucosal immunology
• 影响因子: 8
• 作者: Rabezanahary,Henintsoa;Moukambi,Félicien;Palesch,David;Clain,Julien;Racine,Gina;Andreani,Guadalupe;Benmadid-Laktout,Ghita;Zghidi-Abouzid,Ouafa;Soundaramourty,Calayselvy;Tremblay,Cécile;Silvestri,Guido;Estaquier,Jérôme
• 通讯作者: Estaquier,Jérôme