HIV-1 EnvLRS: a scalable, sequence-based assay for in-depth assessment of HIV-1 bNAb resistance

HIV-1 EnvLRS：一种可扩展、基于序列的检测方法，用于深入评估 HIV-1 bNAb 耐药性

基本信息

批准号：
10324540
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：
2021-07-23 至 2023-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10324540
关键词：
AIDS clinical trial group Acquired Immunodeficiency Syndrome Address Anti-Retroviral Agents Antibodies Archives Base Sequence Biological Assay CD4 Positive T Lymphocytes Cells Chemistry Clinical Clinical Trials Clonality DNA Data Development Diagnostic Disease Progression Dose Dyes Emulsions Epitopes Formulation Foundations Frequencies Generations Genes Genetic Recombination Genomic DNA HIV HIV Infections HIV Seropositivity HIV envelope protein HIV-1 Immune system Individual Institutes Left Leukapheresis Measurement Microfluidics Minor Molecular Participant Performance Peripheral Blood Mononuclear Cell Persons Pharmaceutical Preparations Phase Phenotype Plasmids Population Recovery Regimen Reproducibility Resistance Retroviridae Safety Sampling Sequence Analysis Series Small Business Innovation Research Grant System Testing Time Variant Viral Viral Vector Virus Replication Wisconsin antiretroviral therapy assay development base bioinformatics pipeline clinical implementation individual patient neutralizing antibody novel novel strategies novel therapeutic intervention phase I trial prediction algorithm resistance mutation side effect single molecule small molecule success virology

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, people living with HIV-1 (PLWH) will progress to AIDS and may ultimately die as a result. Combination antiretroviral therapy (ART) with small-molecule drugs is extremely effective at stopping the replication of HIV-1 in infected individuals but requires daily dosing often with considerable side effects. Importantly, despite the success of this approach 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 long-lived CD4+ T cells at extremely low frequencies. These latently infected cells are not targeted by current small-molecule ART regimens. As a result, PLWH must remain on lifelong antiretroviral therapy. Broadly neutralizing antibodies targeting critical epitopes in HIV-1 Env (HIV-1 bNAbs) are currently being developed as a potential approach to eliminate latent HIV-1 and/or as an alternative to small-molecule ART. HIV-1 bNAbs offer several advantages over traditional small-molecule ART, including the potential for long-acting formulations, reduced side effects, and the potential to eliminate latently infected cells over time. However, a major challenge to the implementation of HIV-1 bNAbs in treatment and cure is pre-existing variation or resistance in the bNAb-targeted epitopes. Scalable clinical tests are needed to determine (1) whether people who will receive HIV-1 bNAbs have pre-existing resistance, and (2) personalize HIV-1 bNAb combinations to each individual. To address this critical unmet need, AccelevirDx is developing the HIV-1 EnvLRS assay as the first scalable sequence-based test to assess HIV-1 bNAb resistance and predict antibody efficacy by in-depth env sequence analysis. Broadly, this proposal aims to (1) analytically qualify AccelevirDx’s novel, proprietary HiFi-dePCR approach for env amplification underlying HIV-1 EnvLRS, (2) determine the reproducibility of the HIV-1 EnvLRS assay of samples from PLWH, and (3) apply the assay to a recently completed ACTG A5340 clinical trial of the HIV-1 bNAb VRC01 in PLWH to assess assay performance and utility.

项目摘要/摘要人免疫缺陷病毒类型1（HIV-1）是一种感染免疫的CD4+ T细胞的逆转录病毒系统。如果不及时治疗，患有HIV-1（PLWH）的人将进展到艾滋病，并最终死去结果。抗逆转录病毒疗法（ART）与小分子药物非常有效地停止感染个体中HIV-1的复制，但需要每天给予可考虑的副作用。重要的是，这种方法成功地抑制了HIV-1复制到临床上无法检测到的水平，抗逆转录病毒疗法无法治愈。这是由于HIV-1在沉默或潜在状态下的持续性在极低的频率下，在长寿命的CD4+ T细胞中。这些潜在感染的细胞不是由当前的小分子艺术方案。结果，PLWH必须保留在终身抗逆转录病毒疗法上。目前，针对HIV-1 Env（HIV-1 BNAB）中关键表位的广泛中和抗体是作为消除潜在的HIV-1和/或作为小分子的替代品的潜在方法艺术。 HIV-1 bnabs比传统的小分子艺术具有多种优势，包括潜力长效公式，副作用减少以及随着时间的推移消除潜在感染细胞的潜力。但是，在治疗和治疗中实施HIV-1 BNABS的主要挑战是已有的 BNAB靶向表位的变化或抗性。需要进行可扩展的临床测试来确定（1）是否会收到HIV-1 BNAB的人是否具有先前的抵抗，以及（2）个性化HIV-1 BNAB 每个人的组合。为了满足这种关键的未满足需求，Accelevirdx正在开发HIV-1 ENVLRS分析是第一个基于可伸缩序列的测试，用于评估HIV-1 BNAB抗性并预测深入ENV序列分析的抗体效率。从广义上讲，该建议旨在（1）分析资格 Accelevirdx的小说，专有的HIFI-DEPCR方法，用于HIV-1 Envlrs的ENV扩增，（2）确定来自PLWH的样品的HIV-1 Envlrs分析的可重复性，（3）将测定应用于A 最近完成了PLWH中HIV-1 BNAB VRC01的ACTG A5340临床试验以评估测定性能和实用程序。