Development of Intact Proviral DNA Assays for SIV and SHIV

SIV 和 SHIV 完整原病毒 DNA 检测的开发

• 批准号: 9907751
• 负责人: Gregory Michael Laird
• 金额: $ 30万
• 依托单位: ACCELEVIR DIAGNOSTICS, LLC
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-12-12 至 2021-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9907751
• 关键词: Acquired Immunodeficiency Syndrome; Adoption; Anatomy; Animals; Anti-Retroviral Agents; Biological; Biological Assay; Biological Markers; Blood; Blood specimen; CD4 Positive T Lymphocytes; Cell Line; Cells; Clinical; Clinical Research; Clinical Trials; Clone Cells; Collaborations; DNA; Data; Development; Diagnostic; Disease remission; Ensure; Evaluation; Flow Cytometry; Frequencies; Genomic DNA; HIV-1; Human; Immune; Immune system; Individual; Infection; Intervention; Karyotype determination procedure; Kinetics; Laboratories; Left; Length; Liquid substance; Macaca; Macaca mulatta; Measurement; Measures; Modeling; Molecular; Monitor; National Institute of Allergy and Infectious Disease; Participant; Performance; Pharmaceutical Preparations; Population; Preclinical Testing; Process; Protocols documentation; Proviruses; Reproducibility; Research; Rest; Retroviridae; Risk; SIV; Sampling; Sampling Studies; Sorting - Cell Movement; Study models; Testing; Therapeutic Effect; Therapeutic Studies; Time; Tissue Sample; Tissues; Translating; United States National Institutes of Health; Universities; Viral Markers; Viremia; Virus; Virus Latency; Withdrawal; antiretroviral therapy; cell bank; curative treatments; data quality; design; integration site; medical schools; memory CD4 T lymphocyte; nonhuman primate; novel; novel strategies; novel therapeutic intervention; peripheral blood; pharmacodynamic biomarker; pre-clinical; preclinical development; preclinical efficacy; primary endpoint; programs; simian human immunodeficiency virus; success; therapeutic candidate; therapeutic target; treatment response; viral rebound; virology

PROJECT SUMMARY/ABSTRACT Human immunodeficiency virus type-1 (HIV-1) is a retrovirus that infects CD4+ T cells of the immune system. If left untreated, HIV-1 infected individuals will progress to AIDS and may ultimately die as a result. Combination antiretroviral therapy is extremely effective at stopping the replication of HIV-1 in infected individuals. Despite the success of this therapy at suppressing HIV-1 replication to clinically undetectable levels, antiretroviral therapy is not curative. This is due to the persistence of HIV-1 in a silent, or latent, state within a subset of CD4+ T cells known as resting memory CD4+ T cells. In this latent state, these infected cells are not targeted by antiretroviral drugs and cannot be eliminated by the immune system. In HIV-1 infected individuals, latently infected CD4+ T cells are found at extremely low frequencies (~1 per million resting memory CD4+ T cells), with the majority found within immune tissues at any given time. This population of latently infected cells is very stable, demanding that HIV-1 infected individuals remain on antiretroviral therapy indefinitely to avoid rebound of viremia. As such, this population of latently infected CD4+ T cells is the main barrier to curing HIV-1 infection. Developing strategies to eliminate latently infected cells is a major focus of the NIH, NIAID, and the HIV- 1 research field. SIV and/or SHIV infected macaques are a critical non-human primate model for studying HIV- 1 persistence and testing novel therapeutic approaches. To effectively demonstrate the efficacy of candidate therapeutics targeting the latent reservoir in these animals, we must be able to measure the frequency of latently infected cells using rapid and accurate assays that can be scaled for widespread use, are amenable to analyzing both peripheral blood and processed tissues, and can be translated to human clinical studies. Accelevir Diagnostics, LLC is therefore working with the Siliciano lab at Johns Hopkins School of Medicine to developing SIV and SHIV adapted intact proviral DNA assays (IPDA) and corresponding controls for use in these critical animal studies. Broadly, the proposal aims to develop and characterize novel cell line controls for the SIV IPDA and SHIV IPDA, qualify the performance of the SIV IPDA and SHIV IPDA, and perform initial evaluation of the IPDA as a pharmacodynamic biomarker in SIV/SHIV infected macaque studies of curative interventions.

项目概要/摘要 人类免疫缺陷病毒 1 型 (HIV-1) 是一种逆转录病毒，可感染免疫系统的 CD4+ T 细胞 系统。如果不及时治疗，HIV-1 感染者将发展为艾滋病并最终可能死亡。 联合抗逆转录病毒疗法对于阻止感染者体内 HIV-1 的复制极为有效 个人。尽管这种疗法成功地将 HIV-1 复制抑制到临床无法检测到的水平， 抗逆转录病毒治疗无法治愈。这是由于 HIV-1 在一定时间内持续处于沉默或潜伏状态。 CD4+ T 细胞的子集，称为静息记忆 CD4+ T 细胞。在这种潜伏状态下，这些受感染的细胞不会 是抗逆转录病毒药物的目标，不能被免疫系统消除。在 HIV-1 感染者中， 潜伏感染的 CD4+ T 细胞的发现频率极低（约百万分之 1 的静息记忆 CD4+ T 细胞） 细胞），其中大多数在任何给定时间都存在于免疫组织中。这群潜伏感染的细胞 非常稳定，要求 HIV-1 感染者无限期地继续接受抗逆转录病毒治疗，以避免 病毒血症反弹。因此，这些潜伏感染的 CD4+ T 细胞群是治愈 HIV-1 的主要障碍 感染。 制定消除潜伏感染细胞的策略是 NIH、NIAID 和 HIV 的主要关注点。 1个研究领域。 SIV 和/或 SHIV 感染的猕猴是研究 HIV 的重要非人类灵长类动物模型 1 坚持并测试新的治疗方法。有效展示候选人的效能 针对这些动物的潜在储存库的治疗方法，我们必须能够测量潜在储存库的频率 使用快速、准确的检测方法检测受感染的细胞，可以扩大规模以供广泛使用，并且可以分析 外周血和处理过的组织，并且可以转化为人类临床研究。阿塞莱韦 因此，Diagnostics, LLC 正在与约翰霍普金斯大学医学院的 Siliciano 实验室合作开发 SIV 和 SHIV 采用完整原病毒 DNA 测定 (IPDA) 和相应的对照，用于这些关键领域 动物研究。总体而言，该提案旨在开发和表征 SIV IPDA 的新型细胞系对照 和 SHIV IPDA，鉴定 SIV IPDA 和 SHIV IPDA 的性能，并对 IPDA 作为 SIV/SHIV 感染猕猴治疗干预研究中的药效生物标志物。