Analysis of properties of HIV-1 subtype C envelope glycoprotein

HIV-1 C亚型包膜糖蛋白的特性分析

• 批准号: 8260473
• 负责人: Nina H. Lin
• 金额: $ 13.76万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-05-01 至 2016-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8260473
• 关键词: AIDS prevention; Accounting; Address; Affect; Antibodies; Antibody Formation; Autologous; Biological; Biological Assay; Blood; Botswana; Breast Feeding; CXCR4 gene; Case-Control Studies; Cells; Child; Clinical; Clinical Data; Collaborations; DNA; Data; Disease Progression; Epidemiology; Epitopes; Evolution; Genes; Genetic; Genetic Determinism; Genetic Variation; Genotype; Glycoproteins; HIV; HIV-1; Heterophile Antibodies; Human Milk; Infant; Infection; Low Prevalence; Maps; Measures; Methods; Minor; Minority; Mothers; Mutation; Pathogenesis; Patients; Pattern; Phenotype; Plasma; Population; Predisposition; Pregnancy; Prevention strategy; Property; Prospective Studies; RNA; Research Personnel; Resolution; Risk; Route; Sample Size; Sampling; Sequence Analysis; Specimen; Surrogate Markers; T cell response; Techniques; Technology; Tropism; V3 Loop; Variant; Vertical Disease Transmission; Viral; Virus; Woman; Work; antiretroviral therapy; base; clinically significant; cohort; cross reactivity; design; disease transmission; genetic analysis; in utero; insight; neutralizing antibody; novel; pressure; prophylactic; public health relevance; therapy development; transmission process; treatment strategy; vaccine development

DESCRIPTION (provided by applicant): Many important biological determinants of HIV-1 disease progression and transmission map to the envelope glycoprotein, including antibody neutralization susceptibility, viral tropism for entry and epitopes for T cell response. Genetic and phenotypic characterizations of the envelope gene suggest a bottleneck effect in the spread of the virus to other body compartments and transmission, resulting in a predominantly homogenous viral population. However, the limitations in current methods to accurately assign HIV-1 coreceptor usage, distinguish genetic variations and detect minor variants in the HIV quasispecies within a patient and between transmission pairs have led to controversial findings. Furthermore, the small patient sample size studied has been too small to make broad generalization regarding mechanisms of HIV transmission and pathogensis. Lastly, these various properties of the envelope gene have been studied predominantly in subtype B infection and less clearly elucidated in HIV-1 subtype C, the most rapidly spreading and prevalent infection worldwide. We hypothesize that a heterogenous HIV-1 population with different envelope sequences and coreceptor usage are transmitted during infection but is not fully characterized and measured by our current available techniques. We propose to use novel and more sensitive methods to determine coreceptor usage and to perform in-depth sequencing and genetic analyses of the envelope gene from a large subtype C clinical cohort from Botswana. The envelope gene in subtype C infection will be studied in longitudinal samples, as well as between plasma-breast milk and mother-infant pairs. We plan to study in greater depth the properties of the HIV-1 subtype C envelope glycoprotein with the following specific aims: 1) identify clinical and genetic determinants of coreceptor switching, 2) assess for correlates of breastfeeding transmission of HIV-1 and 3) examine pattern of viral transmission among mother-to-child transmitting pairs occurring through different routes of MTCT using ultradeep sequencing. The results of this study will further the understanding of viral evolution in the context of transmission and disease progression, identify clinical correlates of transmission and disease progression, and ultimately give insights into potential strategies of prevention, treatment and vaccine development in those parts of the world most affected by HIV. PUBLIC HEALTH RELEVANCE (provided by applicant): Understanding mechanisms of HIV pathogenesis, transmission and clinical progression will have public health relevance by guiding the design of HIV prevention and treatment strategies.

描述（由申请人提供）：HIV-1疾病进展和传播图的许多重要生物决定因素到包膜糖蛋白，包括抗体中和易感性，进入病毒性的敏感性以及用于T细胞反应的表位。包膜基因的遗传和表型表征表明，病毒向其他身体室和传播的传播产生瓶颈影响，导致主要同质病毒种群。然而，当前方法中准确分配HIV-1共肽的使用，区分遗传变异并检测患者中HIV准蛋白酶中的次要变异的局限性导致了有争议的发现。此外，所研究的小型患者样本量太小，无法在HIV传播和病原体机制方面进行广泛的概括。最后，包膜基因的这些各种特性主要在亚型B感染中进行了研究，并且在HIV-1亚型C中阐明了，这是全球最快传播和流行的感染。我们假设具有不同的包膜序列和共肽使用情况的异质HIV-1种群在感染过程中会传播，但并未通过我们当前的可用技术来完全表征和测量。我们建议使用新型和更敏感的方法来确定从博茨瓦纳的大型亚型C临床队列中对神经基因的深入测序和遗传分析。亚型感染中的包膜基因将在纵向样品中以及血浆乳脂和母含母牛奶对之间进行研究。我们计划更深入地研究HIV-1亚型C包膜糖蛋白的特性，其特定目的：1）确定康复受体转换的临床和遗传决定因素，2）评估HIV-1和3的母乳喂养传播的相关性，检查使用不同序列的母子传播的病毒传播模式，使用不同的序列发生了不同的序列。这项研究的结果将进一步了解传播和疾病进展，确定传播和疾病进展的临床相关性，并最终深入了解世界上受艾滋病毒影响最大的地区的潜在预防，治疗和疫苗发育的潜在策略。 公共卫生相关性（由申请人提供）：通过指导预防艾滋病毒和治疗策略的设计，了解HIV发病机理，传播和临床进展的机制将具有公共卫生相关性。