BIOMATHEMATICAL ANALYSIS OF VIRAL DYNAMICS AND EVOLUTION

对于HIV感染，生物数学方法在产生可检验的假说方面起了重要作用 关于病毒的持久性和进化，提供对病毒动力学和发病机制的见解， 病毒序列的分析这导致收集越来越详细和复杂的数据， 病毒和宿主的遗传变异，这就需要发展更符合生物学实际的 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， 转化研究计划，以调查艾滋病毒感染的自然史和发病机制。的 RO1 AI047745奖，"病毒动力学和进化的生物数学分析"，提供了数学 和统计支持，以解释数据，并帮助设计新的研究。 我们建议继续开发生物数学模型，以帮助解释病毒和宿主的遗传变异 在逃避治疗和免疫系统的背景下，将这些模型整合到几个临床 研究艾滋病毒感染的各种设置有关的照顾艾滋病毒感染者：1。全长 HIV-1基因组序列将从最近感染HIV的个体中获得， 在全基因组水平上描述感染早期病毒进化的自然史。2. 高分辨率人类白细胞抗原（HLA）单倍型和各种遗传多态性参与 免疫应答将从最近感染HIV的个体获得。这些数据将用于 确定宿主遗传变异在驱动逃逸突变和HIV自然史中的作用。3.一 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， 服务利用率研究将用于生成病毒之间相关性的统计模型 基因型、表型、病毒载量和治疗方案。这些模型将提供关于艾滋病毒如何 对多种抗病毒药物产生耐药性，以及病毒耐药性突变对病毒适应性的影响。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。生殖器 分泌物是传播艾滋病毒的主要来源，关于艾滋病毒在分泌物中的区室化的信息， 男性生殖道将帮助我们了解艾滋病毒传播的生物决定因素。艾滋病毒 中枢神经系统与艾滋病痴呆症有关;我们将研究病毒的遗传变化 与嗜神经性表型相关。

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 RO1 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.