Project 3 - Dynamics of latent HIV-1 reservoirs: High resolution antigenic mapping and strategies to block rebound

摘要-项目3 全世界约有4000万人感染艾滋病毒/艾滋病；然而，保护性疫苗或有效的 尽管进行了40年的紧张研究，但治愈方法仍然难以捉摸。HIV-1通过其自身的功能逃避免疫系统 在感染和复制过程中结构的快速演变。静息记忆中的潜伏库(Rm)CD4T 细胞是治愈HIV-1感染的主要障碍。在感染早期建立的潜伏水库是 非常稳定，尽管接受了长期的抗逆转录病毒治疗(ART)，但仍持续存在。当潜伏感染RMCD4时 T细胞在体内被激活，它们可以再次开始产生艾滋病毒病毒粒子，导致病毒呈指数增长 如果艺术被打断，病毒血症就会反弹。根除这种潜伏的病毒库，以治愈艾滋病毒- 1一直是一个长期追求的目标，但很难实现。另一种方法是延迟或减少 从潜伏的蓄水池反弹，允许持续的无抗逆转录病毒治疗缓解。西里西亚诺实验室最近的一项研究表明 显示针对HIV-1包膜(Env)蛋白的自体中和抗体(AnAbs)抑制 大量但易变的水库病毒在体外生长。这种影响归因于 单抗的中和活性，为单抗预防病毒的可行性提供了原理依据 来自潜在储集层的反弹。此外，通过证明anAbbs阻止了实质性的 潜伏水库中复制能力强的病毒的种群，这些结果有效地减少了 控制反弹到对单抗具有抵抗力的水库病毒子集的问题的严重程度。在……里面 在这个项目中，我们将可视化单抗与敏感病毒环境的结合。此外，我们将确定 抗单抗病毒包膜蛋白的原子级结构研究 抵抗，并确定他们的脆弱性。因此，这项研究的总体目标是对原子水平的理解 抗体介导的控制从潜伏的HIV-1储存库反弹。为了实现这一目标，我们的目标将是1) 定义抑制大量复制群体生长的单抗的表位特异性- 潜伏的HIV-1储存库中的有能力的前病毒；2)确定反弹病毒对 AnAbs的中和作用；以及3)定义HIV-1感染者的Anab反应的演变 了解它对潜伏病毒库播种的影响以及对反跳性病毒血症的影响。在巅峰时刻 在这项研究中，我们期望从结构和抗原性上确定Anab耐药的共同特征 环境，可以有针对性地防止反弹。

Abstract – Project 3 Approximately 40 million people worldwide are living with HIV/AIDS; however, a protective vaccine or functional cure remain elusive despite four decades of intense research. HIV-1 evades the immune system through its rapid structural evolution during infection and replication. The latent reservoir in resting memory (RM) CD4+ T cells is the major barrier to curing HIV-1 infection. Established early during infection, the latent reservoir is extremely stable, and persists despite long-term antiretroviral therapy (ART). When latently infected RM CD4+ T cells are activated in vivo, they can begin to produce HIV virions again, resulting in exponential viral growth and rebound viremia if ART has been interrupted. Eradicating this latent viral reservoir to achieve cure from HIV- 1 has been a long-sought goal that has been difficult to achieve. An alternate approach is to delay or reduce rebound from latent reservoirs allowing sustained ART-free remission. A recent study from the Siliciano lab has shown that autologous neutralizing antibodies (anAbs) directed at the HIV-1 Envelope (Env) protein suppress outgrowth of a substantial but variable fraction of reservoir viruses in vitro. This effect was attributed to neutralizing activity of anAbs, and provides proof-of-principle for the feasibility of Ab-mediated prevention of viral rebound from latent reservoirs. Moreover, by demonstrating that anAbs block the outgrowth of a substantial population of the replication-competent viruses in the latent reservoir, these results effectively reduce the magnitude of the problem of controlling rebound to the subset of reservoir viruses that are resistant to anAbs. In this project, we will visualize the binding of anAbs to the Envs of sensitive viruses. Further, we will determine atomic level structures of Envs from the viruses resistant to anAbs to understand the molecular basis for their resistance, and to define their vulnerabilities. Thus, the overall goal of this study is an atomic level understanding of antibody-mediated control of rebound from latent HIV-1 reservoirs. To achieve this goal, we will aim to 1) define the epitope specificities of anAbs that suppress outgrowth of a substantial population of the replication- competent proviruses in the latent HIV-1 reservoir; 2) define mechanisms of resistance of rebound viruses to neutralization by anAbs; and 3) define the evolution of the anAb response in HIV-1 infected individuals to understand its effect on the seeding of the latent reservoir and its impact on rebound viremia. At the culmination of this study, we expect to have defined, structurally and antigenically, the common features of the anAb resistant Envs that the can be targeted to prevent rebound.