BIOMATHEMATICAL ANALYSIS OF VIRAL DYNAMICS AND EVOLUTION

病毒动力学和进化的生物数学分析

• 批准号: 8011069
• 负责人: DOUGLAS D RICHMAN
• 金额: $ 42.88万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-08-20 至 2011-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8011069
• 关键词: AIDS Dementia Complex; Anatomy; Antiviral Agents; Automobile Driving; Award; Biological; CCL3L1 gene; Caring; Cerebrospinal Fluid; Clinical; Clinical Data; Clinical Research; Collection; Complex; Data; Data Set; Databases; Development; Drug resistance; Evolution; Genetic Polymorphism; Genetic Variation; Genome; Genotype; HIV; HIV Infections; HIV-1; HLA Antigens; Haplotypes; Immune response; Immune system; Individual; Infection; Length; Link; Male Genital Organs; Modeling; Multiple Viral Drug Resistance; Mutation; Natural History; Neuraxis; Pathogenesis; Pattern; Phenotype; Plasma; Play; Regimen; Resolution; Role; Satellite Viruses; Source; Staging; Statistical Models; Therapeutic; Translational Research; Viral; Viral Load result; cost; design; fitness; genital secretion; genome-wide; insight; mathematical model; neurotropic; programs; resistance mutation; response; service utilization; transmission process; viral resistance

DESCRIPTION (provided by applicant): For HIV infection, biomathematical approaches have been instrumental in generating testable hypotheses regarding viral persistence and evolution, in providing insights into viral dynamics and pathogenesis, and in the analysis of viral sequences. This has led to the collection of increasingly detailed and complex data on viral and host genetic variation, which necessitates the development of more biologically realistic mathematical and statistical models of HIV dynamics and evolution. At UCSD we have developed a number of translational research programs to investigate the natural history and pathogenesis of HIV infection. The award of R01 AI047745, "Biomathematical analysis of viral dynamics and evolution," provided mathematical and statistical support to interpret the data and to aid in the design of new studies. We propose to continue to develop biomathematical models to help interpret viral and host genetic variation in the context of escape from therapy and the immune system, integrating these models into several clinical studies of HIV infection in a variety of settings relevant to the care of HIV infected individuals: 1. Full-length sequences of the HIV-1 genome will be obtained from individuals with recent HIV infection in order to describe the natural history of viral evolution during the early stages of infection at a genome-wide level. 2. High resolution human leukocyte antigen (HLA) haplotypes and various genetic polymorphisms involved in immune responses will be obtained from individuals with recent HIV infection. These data will be used to determine the role of host genetic variation in driving escape mutations and the natural history of HIV. 3. A large dataset of viral genotypes, phenotypes and clinical data from over 1000 subjects in the HIV Cost and Services Utilization study will be used to generate statistical models of the correlations between viral genotype, phenotype, viral load, and therapeutic regimen. These models will provide information on how HIV evolves resistance to multiple antiviral agents, and the impact of viral resistance mutations on viral fitness. 4. We will study viral dynamics and evolution in (a) the male genital tract and (b) cerebrospinal fluid. As genital secretions are the major source of transmitted HIV, information on the compartmentalization of HIV within the male genital tract will help us understand the biological determinants of HIV transmission. HIV in the central nervous system is associated with HIV dementia; we will investigate genetic changes in the virus associated with a neurotropic phenotype.

描述（由申请人提供）：对于HIV感染，生物学方法对生成有关病毒持久性和进化的可检验的假设有助于对病毒动力学和发病机理的见解以及病毒序列的分析。这导致收集了有关病毒和宿主遗传变异的日益详细且复杂的数据，这需要开发更现实的HIV动力学和进化的更现实的数学和统计模型。在UCSD，我们开发了许多翻译研究计划，以研究HIV感染的自然病史和发病机理。 R01 AI047745的奖项，“病毒动态和进化的生物学分析”，提供了数学和统计支持，以解释数据并帮助设计新研究。我们建议继续开发生物理性模型，以帮助解释逃避治疗和免疫系统的逃脱背景下的病毒和宿主遗传变异，将这些模型纳入与HIV感染个体的各种环境中HIV感染的几项临床研究：1。1。在HIV-1。在最近的HIV感染中相关的全长序列，在HIV中，在HIV中获得了疗程，以描述HIV的自然效果。全基因组水平。 2。高分辨率人白细胞抗原（HLA）单倍型和与近期HIV感染的个体有关的参与免疫反应的各种遗传多态性。这些数据将用于确定宿主遗传变异在驱动逃生突变和HIV的自然历史中的作用。 3。来自1000多名受试者的病毒基因型，表型和临床数据的大量数据集将用于生成病毒基因型，表型，病毒负荷和治疗方案之间相关性的统计模型。这些模型将提供有关HIV如何发展对多种抗病毒剂的耐药性以及病毒抗性突变对病毒适应性的影响的信息。 4。我们将研究（a）男性生殖道和（b）脑脊液的病毒动力学和进化。由于生殖器分泌是传播艾滋病毒的主要来源，因此关于男性生殖道内艾滋病毒分区化的信息将有助于我们了解艾滋病毒传播的生物学决定因素。中枢神经系统中的HIV与HIV痴呆有关。我们将研究与神经性表型相关的病毒的遗传变化。