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 细胞如果不及时治疗，HIV-1 感染者 (PLWH) 将发展为艾滋病并最终可能死亡。结果，抗逆转录病毒疗法（ART）与小分子药物的联合治疗对于阻止病毒非常有效。 HIV-1 在感染者体内复制，但需要每天给药，通常会产生相当大的副作用。重要的是，尽管这种方法成功地将 HIV-1 复制抑制到临床无法检测到的水平水平，抗逆转录病毒治疗无效，这是由于 HIV-1 持续处于沉默或潜伏状态。以极低的频率存在于长寿命的 CD4+ T 细胞中，这些潜伏感染的细胞不是目标。因此，感染者必须终身接受抗逆转录病毒治疗。目前，针对 HIV-1 Env 中关键表位的广泛中和抗体 (HIV-1 bNAb) 正在开发作为消除潜伏 HIV-1 的潜在方法和/或作为小分子的替代品 ART 与传统小分子 ART 相比，HIV-1 bNAb 具有多种优势，包括潜在的治疗潜力。长效配方，减少副作用，并有可能随着时间的推移消除潜伏感染的细胞。然而，在治疗和治愈中实施 HIV-1 bNAb 的一个重大挑战是预先存在的需要可扩展的临床测试来确定 bNAb 靶向表位的变异或耐药性 (1)。将接受 HIV-1 bNAb 的人是否预先存在耐药性，以及 (2) 个性化 HIV-1 bNAb 为了满足这一未满足的关键需求，AcceleviDx 正在开发 HIV-1。 EnvLRS 测定是第一个可扩展的基于序列的测试，用于评估 HIV-1 bNAb 耐药性并预测通过深入的 env 序列分析来确定抗体功效总的来说，该提案的目的是 (1) 进行分析鉴定。 AccelevirDx 的新型专有 HiFi-dePCR 方法用于 HIV-1 EnvLRS 的环境扩增，(2) 确定 PLWH 样本的 HIV-1 EnvLRS 的重现性，并进行测定 (3) 将测定应用于最近在 PLWH 中完成了 HIV-1 bNAb VRC01 的 ACTG A5340 临床试验，以评估检测结果性能和实用性。