Immunity to novel T/F SHIVs: variability in the co-evolution of virus and host immunity

对新型 T/F SHIV 的免疫：病毒和宿主免疫共同进化的变异性

基本信息

批准号：
10200002
负责人：
GARNETT H KELSOE
金额：
$ 77.7万
依托单位：
DUKE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-07-01 至 2022-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10200002
关键词：
Acquired Immunodeficiency Syndrome Affinity Age Anecdotes Antibodies Antibody Formation Antibody Response Antigens Autologous B-Lymphocytes Binding Cell Lineage Cells Clone Cells Cloning Data Correlations Development Dose Evolution Experimental Models Failure Generations Genetic study Glycoproteins Goals HIV HIV-1 Health Human Humoral Immunities Immune Immune response Immunity Impairment Individual Infection Knowledge Laboratories Macaca Macaca mulatta Maps Memory Methods Molecular Molecular Cloning Natural History Nature Pathway interactions Patients Pattern Plasma Population Problem Solving Production Reproducibility Rhesus Route Serology Societies Specificity Structure of germinal center of lymph node V(D)J Recombination Vaccination Vaccine Design Vaccines Viral Virus Virus Diseases Virus Replication Work base cohort design experimental study infected B cell innovation neutralizing antibody new technology novel novel strategies pandemic disease pre-clinical response simian human immunodeficiency virus stem virus envelope virus host interaction

项目摘要

Statement of Work The HIV-1 pandemic is a global threat and effective vaccination is the most likely pathway to its control. While vaccines that induce broadly neutralizing antibodies (bNAbs) against HIV could be transformative for intervening in the HIV pandemic, no vaccine has been shown to induce HIV-1 bNAbs. Indeed, we do not even understand how bNAb responses arise in rare, HIV-1 infected patients. In part our failure to understand HIV-1 immunity and the generation of bNAb responses can be traced to the absence of a suitable experimental model to study virus:host interaction. Most simian-human immunodeficiency viruses (SHIVs) bearing envelope (Env) glycoproteins from primary HIV-1 strains do not infect rhesus macaques (RMs). This failure reflects low affinity for rhesus CD4 (rhCD4) resulting in impaired virus entry into rhCD4+ cells. We have solved the issue of Env-rhCD4 binding and demonstrated productive infection in RMs by SHIVs with T/F Env glycoproteins, including those that elicit broadly neutralizing antibodies (bnAbs) in humans. The goal of this study is to study infection and immunity in rhesus macaques infected with molecular clones of T/F SHIVs to determine whether patterns of co-evolution by virus and host immunity in individual macaques are similar or unique. This issue is crucial in predicting the efficacy of “lineage design” vaccines.

工作说明书 HIV-1 大流行是一种全球性威胁，有效的疫苗接种是控制其最有可能的途径。诱导针对 HIV 的广泛中和抗体（bNAb）的疫苗可能会带来变革干预艾滋病毒大流行，目前还没有疫苗能够诱导艾滋病毒-1 bNAbs，事实上，我们甚至没有。了解罕见的 HIV-1 感染患者如何产生 bNAb 反应，部分原因是我们未能了解 HIV-1。免疫和 bNAb 反应的产生可以追溯到缺乏合适的实验研究病毒：宿主相互作用的模型大多数猿猴-人类免疫缺陷病毒（SHIV）都有包膜。 (Env) 原代 HIV-1 毒株的糖蛋白不会感染恒河猴 (RM)，这一失败反映了低水平。对恒河猴 CD4 (rhCD4) 的亲和力导致病毒进入 rhCD4+ 细胞受损，我们已经解决了这个问题。 Env-rhCD4 结合并证明 SHIV 具有 T/F Env 糖蛋白对 RM 进行有效感染，包括那些在人体中引发广泛中和抗体 (bnAb) 的抗体。本研究的目的是研究。感染 T/F SHIV 分子克隆的恒河猴的感染和免疫以确定是否个体猕猴中病毒和宿主免疫的共同进化模式是相似或独特的。对于预测“谱系设计”疫苗的功效至关重要。