High-resolution definition of B cell responses to HIV Env for immunogen design

项目摘要 针对HIV env的广谱中和抗体(BNAbs)的诱导是主要的方法之一。 HIV-1疫苗开发面临的挑战。然而，作为疫苗的一个组成部分，HIV-1 Env会引起 到目前为止，大多数临床前和临床研究中的中和广度和效力有限。这个 人类免疫缺陷病毒感染者第二代bNAbs的分离及鉴定 它们在env上的同源表位，为理解 诱导bNAb反应的潜在机制。作为功能最强大的 HIV env的保守和可获得的元件，即受体结合部位，即CD4 结合部位(CD4bs)在病毒与受体结合过程中起着至关重要的作用 在自然感染中成为bNAb反应的易受攻击的目标。VRC01类bNAbs，一个子集 从45名捐赠者和大量其他艾滋病毒感染者中分离出的CD4b bNAbs 支持以VRC01类bNAbs作为疫苗模板的前提。但是，当前 基于环境的免疫原不能通过以下途径诱导VRC01类bNAb反应 接种疫苗。推测的VRC01类bNAb生殖系前体(GVRC01)经常显示 对典型的环境免疫原亲和力弱或没有明显的亲和力。因此，免疫原修饰 包括有效地激活、选择性地扩展和精确地引导的方法 BNab生殖系前体(生殖系靶向)是CD4b bNAb激发所需的，但尚未满足 只取得了有限的成功。在上一个资助期间，我们建立了一个以环境为基础的小组 具有良好抗原性的设计免疫原可诱导CD4b bNAb反应。在这 建议，我们的目标是通过一个创新的计划来扩大我们的努力，该计划包括以下内容 三个相辅相成的特异性目的：(1)研究新奇病毒的免疫原性 免疫原/方案在bNAb种系BCR敲门小鼠中的应用；(2)研究 新型免疫原在豚鼠体内的免疫原性及携带非霍乱弧菌的OmniMouse2模型 (3)探索C3/V4新的中和表位。 作为潜在的bNAb反应目标的环境区域。我们相信，通过这项研究，我们将 (I)有助于彻底了解B细胞对艾滋病的基本反应 接种疫苗和自然感染后的HIV-1Env；和(Ii)贡献新的免疫原， 新的疫苗目标，优化的疫苗接种方案，提高了中和力 以保守的环境元件为目标的响应。

Project Summary The elicitation of broadly neutralizing antibodies (bNAbs) against HIV Env is one of the major challenges of HIV-1 vaccine development. As a vaccine component, HIV-1 Env however elicits limited neutralizing breadth and potency in most pre-clinical and clinical studies to date. The isolation of second generation of bNAbs from HIV-infected individuals, and characterization of their cognate epitopes on Env, offer a tremendous opportunity for understanding the mechanisms underlying the elicitation of bNAb responses. As one of the most functionally conserved and accessible elements of the HIV Env, the receptor binding site, namely CD4 binding site (CD4bs), plays a crucial role for virus engagement with receptor CD4 while serves as a vulnerable target for bNAb response in natural infections. VRC01-class bNAbs, a subset of CD4bs bNAbs isolated from donor 45 and numerous other HIV-infected individuals strongly supports the premise of utilizing VRC01-class bNAbs as vaccine template. However, current Env-based immunogens are not capable of eliciting potent VRC01-class bNAb response via vaccination. The inferred VRC01- class bNAb germline precursors (gVRC01) often display weak or no apparent affinity to prototypical Env immunogens. Thus, immunogen modifications including approaches for efficiently activating, selectively expanding, and precisely shepherding bNAb germline precursors (germline targeting) are needed for CD4bs bNAb elicitation, yet met with limited success. During the last funding period, we established a panel of Env-based designer immunogens with desirable antigenicity for eliciting CD4bs bNAb response. In this proposal, we aim to extend our effort by an innovative program consisting of the following three complementary specific aims: (1) to investigate the immunogenicity of novel immunogens/regimens in bNAb germline BCR knockin mice; (2) to investigate the immunogenicity of novel immunogens in guinea pigs and OmniMouse2 model that carries un- rearranged human antibody loci; and (3) to explore a novel neutralizing epitope in the C3/V4 region of the Env as potential bNAb response target. We believe that through this study we will (i) contribute to the thorough understanding of the basic aspects of the B cell response to the HIV-1 Env following vaccination and natural infection; and (ii) contribute new immunogens, new vaccine target, and optimized vaccination regimens leading to improved neutralizing responses targeting conserved Env elements.