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.



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