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

工作说明书 艾滋病毒-1大流行是一种全球性威胁，有效的疫苗接种是最有可能控制它的途径。而当 诱导针对HIV的广谱中和抗体(BNAbs)的疫苗可能会对 在干预艾滋病毒大流行的过程中，没有任何疫苗被证明能够诱导HIV-1bNAbs。事实上，我们甚至不知道 了解罕见的HIV-1感染患者的bNAb反应是如何产生的。在一定程度上，我们对HIV-1的认识不足 免疫和bNAb反应的产生可以追溯到缺乏合适的实验 研究病毒的模型：宿主相互作用。大多数猴-人类免疫缺陷病毒(SHIV)都有包膜 来自HIV-1主要毒株的(Env)糖蛋白不感染恒河猴(RMS)。这一失败反映出低迷 与恒河猴CD4的亲和力(RhCD4)导致受损的病毒进入rhCD4+细胞。我们已经解决了 通过T/F env糖蛋白与env-rhCD4结合，证实SHIV在RMS中的生产性感染。 包括那些在人类中引起广泛中和抗体(BNAbs)的抗体。本研究的目的是研究 以确定T/F SHV分子克隆感染恒河猴后的感染和免疫 单个猕猴体内病毒和宿主免疫的共同进化模式是相似的或独特的。这个问题是 对预测“世系设计”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.