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

工作说明书 HIV-1大流行是一个全球性威胁，有效的疫苗接种是控制它的最可能途径。而 诱导针对HIV的广泛中和抗体（bNAb）的疫苗可能是变革性的， 在干预HIV大流行中，没有疫苗显示诱导HIV-1 bNAb。其实，我们并不 了解bNAb反应如何在罕见的HIV-1感染患者中产生。部分原因是我们对HIV-1的不了解 免疫力和bNAb反应的产生可以追溯到缺乏合适的实验 研究病毒与宿主相互作用的模型。大多数猴-人免疫缺陷病毒（SHIV） (Env)来自原代HIV-1毒株的糖蛋白不感染恒河猴（RM）。这一失败反映了低 对恒河猴CD 4（rhCD 4）的亲和力导致病毒进入rhCD 4+细胞受损。我们已经解决了 Env-rhCD 4结合，并证明了具有T/F Env糖蛋白的SHIV在RM中的生产性感染， 包括在人体中引发广泛中和抗体（bnAb）的那些。本研究的目的是研究 感染和免疫的恒河猴感染T/F SHIV的分子克隆，以确定是否 在单个猕猴中，病毒和宿主免疫的共同进化模式是相似或独特的。这个问题 这对预测“谱系设计”疫苗的效力至关重要。

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.