BIOMATHEMATICAL ANALYSIS OF VIRAL DYNAMICS AND EVOLUTION

对于艾滋病毒感染，生物数学方法在产生可检验的假说方面发挥了重要作用。 关于病毒的持久性和进化，在提供对病毒动力学和发病机制的见解方面，以及在 对病毒序列的分析。这导致收集了越来越详细和复杂的关于 病毒和宿主的遗传变异，这就需要开发出更符合生物学意义的 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，我们开发了一系列 翻译研究计划，以调查艾滋病毒感染的自然历史和发病机制。这个 RO1AI047745的获奖作品《病毒动力学和进化的生物数学分析》提供了数学上的 和统计支持，以解释数据和帮助设计新的研究。 我们建议继续开发生物数学模型来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，将这些模型集成到几个临床 与艾滋病毒感染者护理相关的各种环境中艾滋病毒感染的研究：1.全文 将从最近感染艾滋病毒的个人那里获得艾滋病毒-1基因组序列，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单倍型与多种基因多态性的关系 免疫应答将从最近感染艾滋病毒的个人那里获得。这些数据将用于 确定宿主基因变异在驱动逃逸突变和艾滋病毒自然历史中的作用。3.A 来自1000多名受试者的艾滋病毒成本和临床数据的病毒基因型、表型和临床数据的大数据集 服务利用率研究将用于生成病毒与病毒之间的相关性的统计模型 基因、表型、病毒载量和治疗方案。这些模型将提供有关艾滋病毒如何 进化出对多种抗病毒药物的耐药性，以及病毒耐药性突变对病毒适应性的影响。4. 我们将研究病毒在(A)男性生殖道和(B)脑脊液中的动力学和进化。作为生殖器 分泌物是传播艾滋病毒的主要来源，关于艾滋病毒在 男性生殖道将帮助我们了解艾滋病毒传播的生物学决定因素。艾滋病病毒在世界各地 中枢神经系统与艾滋病毒痴呆有关；我们将研究病毒的基因变化 与嗜神经性表型有关。

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.