Decay rate of archived HIV-1 drug resistance mutations

存档的 HIV-1 耐药突变的衰减率

基本信息

批准号：
8603455
负责人：
David Allenberg Katzenstein
金额：
$ 7.85万
依托单位：
STANFORD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-05-17 至 2015-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8603455
关键词：
AIDS clinical trial group Address Affect Alleles Antiviral Agents Archives Biological Assay CD4 Lymphocyte Count CD4 Positive T Lymphocytes Chemistry Clinical Consensus DNA Data Detection Drug resistance Enrollment Exposure to Failure Frequencies Future Genotype HIV HIV Infections HIV-1 Human Genome Immune Individual Label Lead Life Link Measures Methods Minority Mutation NNRTI-resistance Patients Peptide Hydrolases Peripheral Blood Mononuclear Cell Pharmaceutical Preparations Plasma Point Mutation Population Prevention Protease Inhibitor Proviruses RNA RNA Sequences RNA-Directed DNA Polymerase Recording of previous events Recycling Regimen Resistance Rest Sampling Single Nucleotide Polymorphism Technology Testing Time Variant Viral Viral Load result Viremia Virus antiretroviral therapy base deep sequencing drug resistant virus efavirenz effective therapy experience innovation next generation sequencing non-nucleoside reverse transcriptase inhibitors public health relevance resistance mutation sample fixation transmission process treatment strategy

AIDS clinical trial group Address Affect Alleles Antiviral Agents Archives Biological Assay CD4 Lymphocyte Count CD4 Positive T Lymphocytes Chemistry Clinical Consensus DNA Data Detection Drug resistance Enrollment Exposure to Failure Frequencies Future Genotype HIV HIV Infections HIV-1 Human Genome Immune Individual Label Lead Life Link Measures Methods Minority Mutation NNRTI-resistance Patients Peptide Hydrolases Peripheral Blood Mononuclear Cell Pharmaceutical Preparations Plasma Point Mutation Population Prevention Protease Inhibitor Proviruses RNA RNA Sequences RNA-Directed DNA Polymerase Recording of previous events Recycling Regimen Resistance Rest Sampling Single Nucleotide Polymorphism Technology Testing Time Variant Viral Viral Load result Viremia Virus antiretroviral therapy base deep sequencing drug resistant virus efavirenz effective therapy experience innovation next generation sequencing non-nucleoside reverse transcriptase inhibitors public health relevance resistance mutation sample fixation transmission process treatment strategy

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项目摘要

DESCRIPTION: Antiretroviral therapy (ART) can reduce plasma HIV-1 levels below the limit of detection of clinical assays. However, incomplete suppression of virus can lead to rapid emergence of significant drug resistance mutations (DRM) that render certain drugs ineffective. The integration of drug resistant viruses into the host DNA and persistence in CD4+ cells in a latent state poses a major obstacle to effective treatment strategies and challenges new universal treatment paradigms for the eradication of HIV infection. The latent cellular reservoir functions as a historical archive of viral genotypes that have previously circulated in the host including provirus harboring DRM. However, little is known about the duration, persistence, and decay of DRM in the proviral reservoir over time. To address these questions, we identified subjects with known dates of virologic failure of Efavirenz-based regimens with emergence of drug resistant viremia (with the K103N mutation). These subjects were previously enrolled in ACTG trials but were subsequently treated with an effective second-line, boosted protease inhibitor-based regimen. CD4 count and viral load were measured and cryopreserved PBMC were collected every 6 months for up to 10 years. Following a failed first-line regimen, we hypothesize that consensus resistance mutations rapidly decay to levels below detection (<20%) in proviral DNA but persist in the latent reservoir with gradual decay over months to years. To test this hypothesis, our proposed study will 1) examine the frequency of DRM in proviral DNA following virologic failure and the detection of DRM in plasma RNA and 2) define the factors that affect fixation, retention, and decay over time and 3) use ultra-deep sequencing to quantify DRM over time in proviral DNA and establish the linkage between reverse transcriptase mutations. The information generated will have important implications for developing future treatment options for ART strategies to reduce clinical failure and mitigate the transmission of drug resistance. !

描述：抗逆转录病毒疗法（ART）可以将血浆HIV-1水平降低到临床测定的检测极限以下。但是，对病毒的不完全抑制会导致显着耐药性突变（DRM）的快速出现，这些突变使某些药物无效。潜在状态下CD4+细胞中耐药病毒的整合和持续性的持续性是有效治疗策略的主要障碍，并挑战了新的普遍治疗范式，以消除HIV感染。潜在的细胞储层是病毒基因型的历史档案，这些档案以前曾在宿主中循环，其中包括携带DRM的病毒病毒。但是，随着时间的流逝，DRM在病毒储层中DRM的持续时间，持久性和衰减知之甚少。为了解决这些问题，我们确定了具有抗耐药性病毒血症（带有K103N突变）的基于Efavirenz病毒性衰竭日期的已知日期的受试者。这些受试者先前已入学ACTG试验，但随后接受了有效的二线基于蛋白酶抑制剂方案的治疗。测量CD4计数和病毒载量，并每6个月收集一次冷冻保存的PBMC，持续10年。在一线方案失败之后，我们假设共识抗性突变迅速衰减至前期DNA的检测水平（<20％），但在潜在储层中持续存在，并且在数月到几年中逐渐衰减。为了检验这一假设，我们提出的研究将研究病毒学衰竭后DRM的频率以及血浆RNA中DRM的检测和2）定义影响固定，保留和衰减的因素，并且随着时间的流逝和3）使用超深测序，以量化临时DNA中的DRM，以量化propiral DNA的链接和在反向转换酶之间的链接中量化。所产生的信息将对为减少临床衰竭并减轻耐药性传播的艺术策略开发未来的治疗选择具有重要意义。呢