HIV-1 Drug Resistance in Different Subtypes

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出现的重组病毒广泛分布在世界各地。应对这一流行病的一项重要措施是在全球范围内扩大抗逆转录病毒治疗方案的覆盖面，有可能向数百万受感染者提供抗逆转录病毒治疗。成功的长期治疗的障碍是耐药性的出现，这是由病毒基因中选择的突变引起的，这既是ART失败的原因，也是ART失败的结果。关于耐药性的知识主要来自美国和欧洲，主要集中在一种HIV-1变异体，亚型B上。然而，全球90%的感染发生在非洲和亚洲资源有限的环境中，其他独特的非B HIV-1亚型占主导地位。有强有力的初步证据表明，治疗前基因型在亚型之间存在差异，并且即使在治疗前，在非B亚型中也可能发生与耐药相关的位置的不同突变。此外，在药物暴露后，在非B亚型中检测到不同的新突变。非B病毒的敏感性和耐药性的信息是至关重要的战略，以维持ART的好处。传播和获得性耐药性的流行率和发病率将推动在资源有限的环境中，公共卫生艾滋病毒治疗方案的诊断检测，初始和二线治疗的决定。该建议的重点是在三个资源有限的环境中建立监测耐药性的科学基础设施，在这些环境中，特定的非B亚型占主导地位。通过这些研究，我们将开发一个强大的HIV-1非B变异体序列数据库，用于基因型分析和耐药突变和模式的表型验证。我们已经设计了一个程序，首先开发质量保证，低成本的耐药性监测策略，使用干燥的过滤器标本进行耐药性测试。这些战略将在泰国、印度和中国实施，以研究HIV-1亚型对目前世卫组织推荐的一线治疗方案耐药性的差异。与Monogram Biosciences合作，我们将使用先进的表型耐药检测方法评估这些样本中突变和模式的重要性。该提案的目标是（i）验证低成本耐药性检测;（ii）确定ART治疗1年和2年后病毒学失败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情况。抗HIV药物耐药性的演变是药物治疗失败的主要原因和后果。大多数关于耐药性的知识来自美国和欧洲对相对罕见的HIV-1亚型B的研究。在资源有限的情况下，大流行占大多数，非B亚型和循环重组形式（CRF）占主导地位。治疗方案使全世界接受抗逆转录病毒疗法的艾滋病患者人数迅速增加。我们的长期目标是确定不同亚型的HIV-1对抗逆转录病毒药物治疗的反应以及亚型在选择和耐药性演变中的意义。

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.