HIV-1 Drug Resistance in Different Subtypes

不同亚型的 HIV-1 耐药性

基本信息

批准号：
8265504
负责人：
Rami Kantor
金额：
$ 11.9万
依托单位：
STANFORD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-09-01 至 2011-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8265504
关键词：
AIDS/HIV problem Acquired Immunodeficiency Syndrome Affect Africa Anti-HIV Agents Anti-Retroviral Agents Antiretroviral resistance Asia Biological Assay Caring China Clinical Data Codon Nucleotides Collaborations Country Data Databases Diagnostic tests Drug Exposure Drug resistance Effectiveness Emergency Situation Epidemic Europe Evolution Failure Frequencies Genbank Genetic Genetic Polymorphism Genotype Goals HIV HIV drug resistance HIV-1 Incidence India Individual Infection International Knowledge Life Link Literature Methods Monitor Mutation Patients Pattern Peptide Hydrolases Persons Pharmaceutical Preparations Phylogenetic Analysis Plasma Population Positioning Attribute Predisposition Prevalence Principal Investigator Protocols documentation Public Health Publishing RNA-Directed DNA Polymerase Recombinants Regimen Research Research Infrastructure Resistance Resources Sampling Science Sensitivity and Specificity Shipping Ships Specimen Surveillance Program Testing Thailand Treatment Failure Treatment Protocols Validation Variant Vertebral column Viral Genes Viremia Virus Work antiretroviral therapy base cohort cost design experience novel pandemic disease population based programs public health relevance recombinant virus resistance mutation response scale up stem transmission process treatment center treatment program treatment strategy working group

项目摘要

DESCRIPTION (provided by applicant): The human immunodeficiency virus (HIV-1) pandemic is due to multiple subtypes and emerging recombinant viruses that are widely distributed around the world. An important response to the epidemic is the global scale-up of access to antiretroviral treatment (ART) programs, potentially delivering ART to millions of infected individuals. A barrier to successful long term treatment is the emergence of drug resistance, caused by mutations selected in viral genes, which are both a cause and a consequence of ART failure. Knowledge about drug resistance comes largely from the US and Europe, focused on one HIV-1 variant, subtype B. However, 90% of infections globally, are in resource limited settings in Africa and Asia, where other distinct, non-B HIV-1 subtypes predominate. There is strong preliminary evidence that pre-therapy genotypes differ among subtypes and that distinct mutations at positions related to resistance may occur, even before treatment, among non-B subtypes. Furthermore, distinct, new mutations are detected in non-B subtypes after drug-exposure. Information on susceptibility and resistance of non-B viruses is critical for strategies to sustain the benefit of ART. Prevalence and incidence of transmitted and acquired drug resistance will drive decisions about diagnostic testing, initial and second-line therapies in public health HIV treatment programs in resource limited settings. The focus of this proposal is to build the scientific infrastructure for surveillance and monitoring of drug resistance in three Resource-limited settings, where specific non- B subtypes predominate. Through these studies we will develop a robust sequence database of HIV-1 non-B variants for genotypic analyses and phenotypic validation of resistance mutations and patterns. We have designed a program to first develop quality assured, low cost drug resistance monitoring strategies using dried filter specimens for resistance testing. These strategies will be implemented in Thailand, India and china, to study differences between HIV-1 subtypes in drug resistance to current first-line, WHO- recommended treatment regimens. In collaboration with Monogram Biosciences we will assess the importance of mutations and patterns in these samples using an advanced method for phenotypic resistance testing. The goals of this proposal are to (i) validate low-cost resistance testing; (ii) determine frequency and patterns of virological failure and drug resistance after 1 and 2 years of ART; and (iii) conduct genotypic analyses and phenotypic validation of subtype-specific mutations and patterns. PUBLIC HEALTH RELEVANCE: The HIV-1 pandemic is a global emergency caused by multiple subtypes. Evolution of anti-HIV drug resistance is the main cause and consequence of drug treatment failure. Most knowledge about drug resistance stems from work in the US and Europe on the relatively uncommon subtype B HIV-1. In resource limited settings, where the majority of the pandemic prevails, non-B subtypes and circulating recombinant forms (CRF) predominate. Treatment access programs are rapidly increasing the numbers of AIDS patients, throughout the world, who are receiving combinations of antiretroviral therapies (ART). Our long-term goal is to determine the how different subtypes of HIV-1 respond to treatment with antiretroviral drugs and the significance of subtype in the selection and the evolution of drug resistance.

描述（由申请人提供）：人类免疫缺陷病毒（HIV-1）大流行是由于多种亚型和新兴的重组病毒引起的，这些病毒广泛分布在世界范围内。对流行病的一个重要反应是全球获得抗逆转录病毒治疗（ART）计划的规模，可能会为数百万受感染的人提供艺术。成功长期治疗的障碍是由病毒基因中选择的突变引起的耐药性的出现，这既是艺术衰竭的原因又是结果。关于耐药性的知识主要来自美国和欧洲，重点是一种HIV-1变体。但是，全球90％的感染中有90％在非洲和亚洲的资源有限的环境中，其他不同的非B HIV-1子类型占主导地位。有强有力的初步证据表明，疗法前基因型在亚型之间有所不同，并且在非B亚型之间，甚至在治疗前，与抗药性相关的位置的不同突变也可能发生。此外，在药物暴露后，在非B亚型中检测到不同的新突变。关于非B病毒的敏感性和抵抗性的信息对于维持艺术利益的策略至关重要。在资源有限的环境中，传播和获得的药物抵抗的患病率和发病率将推动有关公共卫生艾滋病毒治疗计划中诊断测试，初始和二线疗法的决定。该提案的重点是在三种资源有限的环境中建立科学基础设施，以监视和监测耐药性，在这种情况下，特定的非B亚型占主导地位。通过这些研究，我们将开发一个可靠的HIV-1非B变体序列数据库，用于基因型分析和抗药性突变和模式的表型验证。我们设计了一个程序，以使用干滤器标本进行阻力测试，首先开发质量确保低成本的耐药性监测策略。这些策略将在泰国，印度和中国实施，以研究HIV-1亚型对当前一线耐药性的差异，谁推荐了治疗方案。与会标生物科学合作，我们将使用高级方法进行表型抗性测试来评估这些样品中突变和模式的重要性。该提案的目标是（i）验证低成本抵抗测试；（ii）确定1和2年的艺术后病毒学衰竭和耐药性的频率和模式；（iii）对亚型特异性突变和模式进行基因型分析和表型验证。公共卫生相关性：HIV-1大流行是由多种亚型引起的全球紧急事件。抗HIV耐药性的进化是药物治疗失败的主要原因和结果。关于耐药性的大多数知识源于美国和欧洲对相对罕见的亚型B HIV-1的工作。在资源有限的设置中，大多数大流行占上风，非B亚型和循环重组形式（CRF）占主导地位。治疗访问计划正在迅速增加世界各地的艾滋病患者人数，他们正在接受抗逆转录病毒疗法（ART）的组合。我们的长期目标是确定HIV-1的亚型如何应对抗逆转录病毒药物的治疗以及亚型在选择和耐药性演变中的重要性。