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艾滋病毒感染的初始阶段，对于破译病毒的发病机制和开发有效的疫苗至关重要，因为疫苗引发的适应性免疫反应预计将在初始阶段对病毒复制和进化发挥主要作用。以前对这一感染早期阶段进行建模的努力一直无法充分利用现有的临床数据，因为目前的模型没有在单一框架中整合病毒复制和序列进化。我们将构建一个同时包含病毒复制动态和病毒序列多样化的艾滋病毒原发感染模型。我们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艾滋病毒感染的时空动态。然后，我们将使用这个模拟来模拟疫苗对宿主免疫控制艾滋病毒感染的影响。在目标1中，将构建一个蒙特卡洛(MC)模拟，说明HIV感染初期的病毒动力学和序列进化。感染细胞的HIV前病毒种群将使用病毒学参数进行模拟，包括动态繁殖率、世代时间和逆转录酶单周期错误率。在目标2中，我们将该模型应用于NIAID支持的默克重组Ad5-HIV Gag/Poll/nef疫苗的IIB阶段评估(STEP研究；默克/HIV疫苗试验网络合作)的数据，以了解为什么这种疫苗在许多试验参与者中诱导出HIV特异性CD8细胞，但对经历突破性感染的人的病毒载量没有影响。我们将使用我们的模型来检验可能解释这种缺乏效力的三个假说：(1)传播毒株和疫苗毒株之间的高抗原距离可能损害了疫苗的效力；(2)病毒逃避疫苗诱导的CD8+T细胞反应可能导致病毒复制增强；(3)疫苗相关的CD4+T细胞激活可能放大了病毒复制，从而抵消了病毒特异性CD8细胞所赋予的潜在好处。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来预测疫苗效力。这些研究有望产生一种新的、全面的艾滋病毒感染计算模型。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随后的艾滋病进展和探索疫苗效力方面发挥着关键作用，但仍知之甚少。该项目将开发一种计算模拟，可用于模拟病毒感染的这一关键阶段。预计该模型将在帮助设计安全有效的艾滋病毒/艾滋病疫苗方面具有重要的实用价值。

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.