IPDA for High-Priority HIV-1 Subtype C to Enable Global Eradication Trials

IPDA 针对高度优先的 HIV-1 C 亚型以实现全球根除试验

基本信息

批准号：
10324486
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
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-07-07 至 2023-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10324486
关键词：
AIDS/HIV problem Acquired Immunodeficiency Syndrome Address Adult Africa African Anti-Retroviral Agents Base Sequence Benchmarking Biological Assay CD4 Positive T Lymphocytes Cells Clinical Cohort Analysis Cohort Studies Collaborations Cryopreservation DNA Data Development Diagnostic Disease remission Europe Frequencies Generations Genomic DNA HIV HIV-1 Immune Immune system Individual Infection Left Legal patent Length Letters Libraries Life Measurement Measures Mediating Military Personnel Molecular Molecular Weight Monitor National Institute of Allergy and Infectious Disease Participant Pattern Performance Peripheral Blood Mononuclear Cell Pharmaceutical Preparations Phase Population Positioning Attribute Prevalence Proviruses Public Health Publishing Regimen Reproducibility Research Rest Retroviridae Sampling Sampling Studies Site Small Business Innovation Research Grant Specificity Testing Time Tissues Treatment Efficacy United States United States National Institutes of Health Viral Viral Load result Viral reservoir Viremia Virus Virus Replication antiretroviral therapy base cohort design digital genome sequencing indexing longitudinal analysis memory CD4 T lymphocyte novel peripheral blood programs research clinical testing side effect success therapeutic target

项目摘要

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. To demonstrate the efficacy of therapeutics targeting the latent reservoir, we must be able to measure the frequency of latently infected cells using rapid and accurate assays that can be scaled for widespread clinical use. Critically, such assays must be capable of accurately measuring the size of the latent reservoir across viral subtypes. Accelevir Diagnostics, LLC has recently developed the IPDA as a novel digital droplet PCR assay to measure intact and defective proviruses in a small sample of peripheral blood. The IPDA was optimized for use in people with subtype B HIV-1 infection, which predominates in the United States and Europe but comprises on a small fraction of people living with HIV-1 worldwide. In this proposal, Accelevir Diagnostics seeks to expand the IPDA coverage to include people living with subtype C HIV-1 infection, which accounts for approximately 50% of all people living with HIV-1 worldwide. Broadly, this proposal aims to perform in-depth proviral sequencing to inform expansion of assay coverage followed by assay design adaptation, performance qualification, and analysis of longitudinally collected samples from people living with subtype C HIV-1 infection. This proposal leverages a close collaboration with the US Military HIV Research Program, enabling access to a unique and cohort of people living with subtype C HIV-1 infection across Africa.

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，并最终可能因此死亡。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水平，抗逆转录病毒治疗没有疗效。这是由于 HIV-1 持续处于沉默或潜伏状态属于 CD4+ T 细胞的一个子集，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是抗逆转录病毒药物的目标，也不能被免疫系统消除。 HIV-1感染者在个体中，发现潜伏感染的 CD4+ T 细胞的频率极低（约百万分之 1）记忆 CD4+ T 细胞），其中大多数在任何给定时间都存在于免疫组织中。这个人口潜伏感染细胞非常稳定，要求 HIV-1 感染者继续接受抗逆转录病毒治疗无限期避免病毒血症反弹。因此，潜伏感染的 CD4+ T 细胞群是主要的治愈 HIV-1 感染的障碍。制定消除潜伏感染细胞的策略是 NIH、NIAID 和 HIV-1研究领域。为了证明针对潜在储库的治疗方法的功效，我们必须能够使用快速、准确的测定法来测量潜伏感染细胞的频率，这些测定法可以扩展临床广泛使用。至关重要的是，此类测定必须能够准确测量潜在的大小跨病毒亚型的储存库。 Accelevir Diagnostics, LLC 最近开发了 IPDA 作为一种新型数字液滴 PCR 检测可测量少量外周血样本中完整和有缺陷的原病毒。国际发展协会针对 B 亚型 HIV-1 感染者进行了优化，该感染在美国和但欧洲仅占全球 HIV-1 感染者的一小部分。在该提案中，Accelevi Diagnostics 寻求扩大 IPDA 覆盖范围，将 C 亚型 HIV-1 感染者纳入其中，这约占全世界 HIV-1 感染者的 50%。总体而言，该提案旨在进行深入的原病毒测序，以扩大检测覆盖范围，然后进行检测设计对从患有这种疾病的人身上纵向收集的样本进行适应、性能鉴定和分析 C 亚型 HIV-1 感染。该提案利用了与美国军方艾滋病毒研究中心的密切合作该计划旨在帮助非洲各地独特的 C 亚型 HIV-1 感染人群。