Modeling HIV Escape from Neutralizing Antibody Respones

描述（由申请人提供）：HIV在体内可以快速逃离中和抗体反应。虽然逃逸促进了病毒在感染患者体内的持续存在，但逃逸中和意味着抗体反应对病毒施加了显著的选择性压力。因此，疫苗增强的体液反应可能对预防感染有效，因为感染病毒的小群体不能迅速进化。有效的疫苗还能诱导显著的异源中和反应。尽管HIV阳性患者的血清通常对HIV的中和具有抗性，但一些个体会产生广泛的反应性中和反应。最近，高通量测定法可以量化中和抗体反应，再加上对HIV-1包膜基因全长克隆的测序能力，可以定量分析自体和异源中和反应，以及它们与病毒遗传变异的关系。我们建议根据来自原发性HIV感染个体的数据，量化HIV-1包膜中的点突变和插入/缺失在病毒逃逸中的作用。中和抗体反应将采用快速、高度可重复的重组病毒/报告基因测定法进行测定，包膜遗传变异将采用基于群体和克隆测序法进行测定。对这些数据的分析提出了一些统计上的挑战。我们将开发统计模型来(a)获得自体中和抗体反应动力学和病毒逃逸模式的定量描述，(b)量化患者血清之间和异源中和病毒之间的差异，并将这种差异与宿主和病毒（例如病毒基因型）因素联系起来。这些模型将考虑到艾滋病毒数据的层次性质，将使用基于样条的方法来捕获非线性效应，并将合并用于审查和测量误差的子模型。

DESCRIPTION (provided by applicant): HIV can rapidly escape neutralizing antibody responses in vivo. Although escape facilitates viral persistence within the infected patient, escape from neutralization implies that the antibody response is exerting significant selective pressure on the virus. Consequently, a vaccine-boosted humoral response may be effective in preventing infection, as the small population of infecting viruses cannot evolve quickly. An effective vaccine will also be able to induce significant heterologous neutralization responses. Although HIV is generally resistant to neutralization by sera from HIV-positive patients, some individuals mount broadly reactive neutralization responses The recent availability of high-throughput assays to quantify neutralizing antibody responses coupled with the ability to sequence full-length clones of the HIV-1 envelope gene permits a quantitative analysis of autologous and heterologous neutralization responses, and their relationship to viral genetic variation. We propose to quantify the roles of point mutations and insertions/deletions in the HIV-1 envelope in viral escape based on data from individuals with primary HIV infection. Neutralizing antibody responses will be measured using a rapid, highly reproducible recombinant virus/reporter assay, and genetic variation in envelope will be measured using both population-based and clonal sequencing. Analysis of these data presents a number of statistical challenges. We will develop statistical models to (a) obtain a quantative description of the dynamics of autologous neutralizing antibody responses and the patterns of viral escape and (b) to quantify variation between patients' sera and between viruses in heterologous neutralization, and relate this variation to host and viral (e.g. viral genotype) factors. These models will take the hierarchical nature of HIV data into account, will use spline-based methods to capture nonlinear effects, and will incorporate submodels for censoring and measurement error.