HIV Incidence Assay via Deep Sequencing and Statistical Tests

通过深度测序和统计测试进行 HIV 发病率测定

• 批准号: 8514506
• 负责人: Ha Youn Lee
• 金额: $ 48.18万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-08-10 至 2015-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8514506
• 关键词: AIDS prevention; AIDS/HIV problem; Acquired Immunodeficiency Syndrome; Acute; Address; Affect; Antibodies; Antibody Formation; Antigens; Area; Avidity; Base Sequence; Behavior; Biological Assay; Biological Markers; Blood; Blood specimen; CD4 Lymphocyte Count; Centers for Disease Control and Prevention (U.S.); Characteristics; Chronic; Clinic; Communities; Computer software; Data; Data Set; Development; Diagnosis; Disease; Enrollment; Epidemic; Evolution; Foundations; Genes; Guidelines; HIV; HIV Infections; HIV prevention trial; Hospitals; Incidence; Individual; Infection; Internet; Intervention; Intervention Trial; Kenya; Kinetics; Knowledge; Lead; Letters; Longitudinal Studies; Macaca; Manitoba; Measures; Modeling; Online Systems; Patients; Plasma; Population Heterogeneity; Prevention; Prevention Research; Preventive Intervention; Publications; Reporting; Research; Research Activity; SIV; Sampling; Scheme; Sequence Analysis; Serological; Staging; Statistical Methods; Testing; Time; Universities; Update; Vaccines; Viral; Viral load measurement; Virus; Washington; Work; base; cohort; deep sequencing; design; innovation; meetings; microbicide; next generation; novel; pyrosequencing; sex; tool

DESCRIPTION (provided by applicant): Our recent studies developed acute sequence evolution model which has been applied to interpret sequence clones derived from 102 subjects with acute HIV subtype B infection, from 69 subjects with acute HIV subtype C infection, and from numerous SIV-infected macaques. Our model enabled an assessment of the sequence diversity in HIV infections originating from a single transmitted viral strain and the estimation on the period of infection, which has been a significant and beneficial contribution to HIV research community. We propose to expand our research activity of modeling intrahost HIV diversification toward the development of a novel assay identifying new, recent HIV infections. In the HIV/AIDS prevention field, it is critical to assess how many people have been recently infected in a given area in order to evaluate the feasibility of prevention and intervention trials. The diagnosis of HIV infection is currently possible from blood samples but reliable assays predicting how long an individual has been infected have not been developed. Various detuned antibody assays, or avidity-based assessments, have been used, assuming that antibody titer and avidity increases with time. However, serologic assays are problematic because (i) the rate of maturation of the antibody response varies between different individuals, (ii) some subjects with low CD4 counts or low virus loads may be inaccurately counted as having recent infection, and (iii) serologic assays can be negatively affected if the infecting virus clade differs from the clade of the antigen used in the assay (this is a particular problem in mixed-clade epidemics). This proposal aims to provide empirical and theoretical foundations for inventing a novel assay that distinguishes new, incident infections from chronic, asymptomatic infections. Major innovations of the proposal include (i) its comprehensive integration of next-generation ultradeep pyrosequencing data and biomathematical modeling and (ii) a novel statistical design estimating the number of founder viruses and the duration of infection. Our proposed study will focus on overcoming two primary barriers to the development of a sequencing based assay. First, the assay potentially mis-classifies early infections with multiple distinct founder strains as chronic infections. Second, it is questionable whether the assay can distinguish incident samples from chronic ones obtained at late stages of infections. We propose to collect a large scale of HIV sequence data from diverse population in different epidemic regions and different stages of infections. Ultradeep sequencing data in conjunction with novel statistical designs will lead us to invent a novel assay that is capable of identifying incident infections. The proposed work will advance HIV prevention research by providing a reliable assay based on the characteristics of intrahost HIV diversification.

描述（由申请人提供）：我们最近的研究开发了急性序列进化模型，该模型已应用于解释源自102名患有急性HIV亚型B感染的受试者，来自69名患有急性HIV亚型C感染的受试者，以及来自许多SIV感染的受试者。我们的模型使艾滋病毒感染的序列多样性源于单个传播病毒株以及对感染周期的估计，这对艾滋病毒研究界做出了重要贡献。我们建议将研究活动扩展到建模HIV内多元化的研究活动，从而开发出一种新的测定法，以鉴定新的，最近的HIV感染。在艾滋病毒/艾滋病预防领域中，至关重要的是要评估有多少人在给定区域中被感染，以评估预防和干预试验的可行性。目前可以从血液样本中诊断出HIV感染，但是可靠的测定方法可以预测未发育的人已经发育了多长时间。假设抗体滴度和同胞随时间增加，已经使用了各种失谐抗体测定或基于亲戚的评估。 However, serologic assays are problematic because (i) the rate of maturation of the antibody response varies between different individuals, (ii) some subjects with low CD4 counts or low virus loads may be inaccurately counted as having recent infection, and (iii) serologic assays can be negatively affected if the infecting virus clade differs from the clade of the antigen used in the assay (this is a particular problem in mixed-clade流行病）。该提案旨在提供经验和理论基础，以发明一种新的测定法，该测定法将新的事件感染与慢性，无症状感染区分开。该提案的重大创新包括（i）其下一代超过旋质测序数据和生物学建模的全面整合，以及（ii）估计创始人病毒数量和感染持续时间的新型统计设计。我们提出的研究将着重于克服基于测序测定的两个主要障碍。首先，该测定可能会错误地分类，以多种不同的创建者菌株作为慢性感染。其次，该测定是否可以将事件样本与在感染后期获得的慢性样本区分开是值得怀疑的。我们建议从不同流行病地区和不同感染阶段收集大量的HIV序列数据。与新颖的统计设计结合结合使用的超模型测序数据将使我们发明能够识别入射感染的新型测定法。拟议的工作将通过基于HIV内艾滋病毒多样化的特征提供可靠的测定方法来推动艾滋病毒预防研究。