Modeling HIV Escape from Neutralizing Antibody Respones

描述（由申请方提供）：HIV可迅速逃避体内中和抗体应答。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，疫苗增强的体液应答可能有效地预防感染，因为感染病毒的小群体不能快速进化。有效的疫苗还将能够诱导显著的异源中和应答。虽然HIV通常对来自HIV阳性患者的血清的中和具有抗性，但一些个体产生广泛反应性中和应答。最近可用的用于定量中和抗体应答的高通量测定与对HIV-1包膜基因的全长克隆进行测序的能力相结合，允许对自体和异源中和应答及其与病毒遗传变异的关系进行定量分析。我们建议量化点突变和插入/缺失的HIV-1包膜中的病毒逃逸的基础上，从个人的数据与原发性HIV感染的作用。将使用快速、高度可重现的重组病毒/报告基因试验测量中和抗体应答，并使用基于群体和克隆测序测量包膜中的遗传变异。 对这些数据的分析提出了一些统计挑战。我们将开发统计模型，以（a）获得自体中和抗体应答的动态和病毒逃逸模式的定量描述，（B）定量异源中和中患者血清之间和病毒之间的变异，并将这种变异与宿主和病毒（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分层性质，将使用基于样条的方法来捕获非线性效应，并将纳入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.