Simulator for Primary HIV Replication and Evolution

描述（由申请人提供）：通过定量计算模型更好地了解HIV感染的初级阶段对于破译病毒发病机制和开发有效疫苗至关重要，因为疫苗引发的适应性免疫反应预计将在初级阶段对病毒复制和进化发挥主要作用。由于目前的模型没有将病毒复制和序列进化整合到一个框架中，因此之前对这种早期感染建模的努力无法充分利用现有的临床数据。我们将构建一个将病毒复制动力学和病毒序列多样化同时结合的原发性HIV感染模型。我们的模型的主要创新将包括(i)全面整合病毒学动力学和序列数据，以及（ii）发明基于网络的软件来可视化HIV感染的时空动态。然后，我们将使用这种模拟来模拟疫苗引起的对HIV感染的宿主免疫控制的影响。在目标1中，将构建一个蒙特卡罗（MC）模拟，说明HIV感染初级阶段的病毒动力学和序列进化。将使用病毒学参数，包括动态繁殖比、生成时间和逆转录酶单周期错误率来模拟感染细胞的HIV病毒种群。在Aim 2中，我们将该模型应用于niaid支持的默克重组Ad5-HIV gag/pol/nef疫苗的IIB期评估数据（STEP研究；默克/HIV疫苗试验网络合作），以了解为什么该疫苗在许多试验参与者中引发了HIV特异性CD8细胞，但对那些经历突破性感染的个体的病毒载量没有影响。我们将使用我们的模型来检验三个可能解释这种功效缺乏的假设：(1)传播毒株和疫苗毒株之间的高抗原距离可能会降低疫苗效力；(2)病毒从疫苗诱导的CD8+ T细胞反应中逃逸可能导致病毒复制增强；(3)疫苗相关的CD4+ T细胞活化可能会放大病毒复制，从而抵消病毒特异性CD8细胞所带来的潜在益处。最后，Aim 3将发明基于网络的模拟工具，用于使用临床数据输入预测疫苗效力。这些研究有望产生一种新的、全面的原发性HIV感染计算模型。公共卫生相关性：人类免疫缺陷病毒（HIV）感染的初始阶段在决定艾滋病的后续进展和探测疫苗效力方面起着至关重要的作用，但人们对这一问题的了解仍然很少。该项目将开发一种可用于模拟病毒感染这一关键阶段的计算模拟。预计该模型将在帮助设计安全有效的艾滋病毒/艾滋病疫苗方面发挥重要作用。

DESCRIPTION (provided by applicant): Better understanding of the primary phase of HIV infection through quantitative computational modeling is crucial for deciphering viral pathogenesis and for developing an effective vaccine, since vaccine-elicited adaptive immune responses are expected to exert their major effects on viral replication and evolution during the primary phase. Previous efforts to model this early stage of infection have been unable to fully exploit available clinical data since current models did not integrate viral replication and sequence evolution in a single framework. We will construct a model for primary HIV infection that will incorporate virus replication dynamics and viral sequence diversification simultaneously. Major innovations of our model will include (i) comprehensive integration of virologic kinetics and sequence data and (ii) invention of web-based software to visualize the spatio-temporal dynamics of HIV infection. We will then use this simulation to model vaccine- elicited effects on host immune control of HIV infection. In Aim 1, a Monte-Carlo (MC) simulation illustrating both viral kinetics and sequence evolution in the primary phase of HIV infection will be constructed. The HIV provirus population of infected cells will be simulated using virologic parameters, including dynamic reproductive ratio, generation time, and reverse transcriptase single cycle error rate. In Aim 2, we apply the model to data from the NIAID-supported phase IIB evaluation of Merck's recombinant Ad5-HIV gag/pol/nef vaccine (STEP Study; Merck/HIV Vaccine Trials Network collaboration) in order to understand why this vaccine elicited HIV-specific CD8 cells in many trial participants but had no effect on virus load in those individuals who experienced breakthrough infections. We will use our model to test three hypotheses that might explain this lack of efficacy: (1) high levels of antigenic distance between the transmitted strain and the vaccine strain may have compromised vaccine efficacy (2) viral escape from vaccine-induced CD8+ T cell responses may have resulted in the enhancement of viral replication or (3) vaccine-related CD4+ T cell activation may have amplified virus replication, thereby offsetting the potential benefit conferred by virus- specific CD8 cells. Finally, Aim 3 will invent web-based simulation tools for prediction of vaccine efficacy using clinical data inputs. These studies are expected to result in a novel and comprehensive computational model for primary HIV infection. PUBLIC HEALTH RELEVANCE: The initial phase of infection with human immunodeficiency virus (HIV) plays a crucial role in determining subsequent progression to AIDS and probing vaccine efficacy, but remains poorly understood. This project will develop a computational simulation that can be used to model this critical phase of virus infection. The model is expected to have important utility in helping to design safe and effective HIV/AIDS vaccines.