BIOMATHEMATICAL ANALYSIS OF VIRAL DYNAMICS AND EVOLUTION

描述（由申请人提供）：对于HIV感染，生物数学方法在生成关于病毒持久性和进化的可测试假设，提供对病毒动力学和发病机制的见解以及对病毒序列的分析方面发挥了重要作用。这导致收集越来越详细和复杂的病毒和宿主遗传变异数据，这就需要开发更符合生物学现实的艾滋病毒动态和进化的数学和统计模型。在加州大学圣地亚哥分校，我们开发了许多转化研究项目来研究HIV感染的自然历史和发病机制。R01 AI047745“病毒动力学和进化的生物数学分析”奖为解释数据和帮助设计新研究提供了数学和统计支持。我们建议继续发展生物数学模型，以帮助解释逃避治疗和免疫系统背景下的病毒和宿主遗传变异，并将这些模型整合到与艾滋病毒感染者护理相关的各种环境下的艾滋病毒感染的几项临床研究中。HIV-1基因组的全长序列将从近期HIV感染的个体中获得，以便在全基因组水平上描述感染早期阶段病毒进化的自然历史。2. 高分辨率人类白细胞抗原（HLA）单倍型和参与免疫反应的各种遗传多态性将从近期感染HIV的个体中获得。这些数据将用于确定宿主遗传变异在驱动逃逸突变和HIV自然历史中的作用。3. 在HIV成本和服务利用研究中，来自1000多名受试者的病毒基因型、表型和临床数据的大型数据集将用于生成病毒基因型、表型、病毒载量和治疗方案之间相关性的统计模型。这些模型将提供关于HIV如何进化出对多种抗病毒药物的抗性，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)脑脊液中的病毒动力学和进化。由于生殖器分泌物是艾滋病毒传播的主要来源，关于艾滋病毒在男性生殖道内划分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；我们将研究与嗜神经表型相关的病毒的遗传变化。

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.