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A method for accurate and sensitive detection of HIV drug-resistant minority variants

一种准确、灵敏地检测 HIV 耐药少数变异的方法

基本信息

批准号：
9139024
负责人：
GARY P. WANG
金额：
$ 25.32万
依托单位：
MEDOSOME BIOTEC, LLC
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-03-15 至 2018-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9139024
关键词：
Anti-Retroviral Agents Base Sequence Bioinformatics Biological Assay CCR5 gene CXCR4 gene Clinical Data Detection Development Dose Drug resistance Evaluation Failure Florida Goals Guidelines HIV HIV drug resistance HIV resistance HIV-1 HIV-1 drug resistance HIV/HCV Hepatitis C co-infection Hepatitis C virus Individual Laboratories Lead Measures Methods Minor Minority Molecular Cloning Morphologic artifacts Mother-to-child HIV transmission NNRTI-resistance Nevirapine Patients Perinatal Pharmaceutical Preparations Phase Population Pregnant Women Preparation Reading Research Resistance Reverse Transcription Risk Sampling Sensitivity and Specificity Sequence Analysis Sequence Determination Site Small Business Technology Transfer Research Specimen Speed Techniques Technology Test Result Testing Universities Variant Viral Work antiretroviral therapy base commercialization cost drug resistant virus improved in vivo inhibitor/antagonist innovation non-nucleoside reverse transcriptase inhibitors novel strategies phase 2 study prevent public health relevance pyrosequencing quality assurance resistance mutation response success

项目摘要

DESCRIPTION (provided by applicant): Drug resistance to HIV is a major threat to achieving long-term viral suppression in HIV+ individuals. Up to 16% of newly infected individuals acquire HIV with resistance to at least one of the major antiretroviral classes, and incomplete viral suppression and virologic failure are often associated with drug resistance. Therefore, current DHHS guideline recommends drug resistance testing before beginning or changing antiretroviral therapy. Genotypic assay based on population or bulk sequencing is the most commonly used method to determine HIV drug resistance mutations. However, because HIV circulates as quasispecies in vivo, current commercial assays are not sensitive in detecting minority drug resistant variants, which are known to compromise clinical response to antiretroviral therapy. Therefore, an accurate and sensitive assay that is capable of detecting drug resistant minority populations is urgently needed to determine the impact of HIV minor variants on viral suppression and guide rational selection of optimal antiretroviral therapy. The objective of this Phase I STTR application is to develop a sensitive assay that can accurately quantify HIV-1 minority variants. Recently, Dr. Wang's (PI, University of Florida) laboratory developed a Single Variant Sequencing (SVS) approach, which takes advantage of the speed and accuracy of the high-throughput MiSeq technology, and a random sequencing tags strategy that removes biases and technical artifacts known to obscure true representations of minority variants. By developing a bioinformatics pipeline that automates analysis of drug resistance calls, his laboratory has applied this SVS approach to quantify minor HCV resistance-associated variants in clinical samples. Medosome Biotec and its research partner at UF hypothesize that this SVS approach can be optimized to quantify minority populations of drug resistant HIV-1 accurately. In Phase I, the team will test this hypothesis by pursuing two Specific Aims: 1) Optimize the SVS method for sensitive and accurate quantification of HIV-1 drug resistance minority variants, and 2) Conduct initial testing of the optimized SVS method using laboratory HIV strains and clinical isolates. The SVS approach for HIV resistance testing is innovative because it will leverage the speed, accuracy, and the long paired-end read capability of MiSeq personal sequencer, and the random sequencing tag method to produce a new HIV-1 resistance assay for quantitative detection of HIV-1 minor variants. If successful, the SVS assay will be validated and developed in Phase II studies. An accurate and sensitive low cost SVS assay will have tremendous commercialization potential, given the global burden of HIV with more than 35 million HIV+ individuals requiring resistance testing at least once.