HIV-1 vaccine-elicited antibodies target envelope glycans

 描述（由申请方提供）：人类免疫缺陷病毒1型（HIV-1）大流行在缺乏预防性疫苗的情况下继续蔓延。抗HIV-1的广泛中和抗体（bnAb）可以预防非人灵长类动物的感染，但迄今为止还没有通过疫苗接种引起。HIV-1包膜被一系列密集的宿主聚糖覆盖，如果被 疫苗诱导的抗体，可以产生bnAb。具有这些特异性的BnAb在自然感染中产生。然而，迄今为止，用于引发抗Env聚糖抗体的疫苗策略已显示聚糖依赖性表位的免疫原性差。在我对用M组共有包膜CON-S（含有相当大比例的高甘露糖）接种的恒河猴的研究中，我已经鉴定了阻断抗聚糖bnAb与HIV-1 Env结合的猕猴血浆抗体。CON-S Env gp 140免疫的猕猴也具有足够的抗体滴度用于检测其血浆中的直接聚糖结合，并且我已经成功地从CON-S Env免疫的动物中分离出聚糖反应性恒河猴单克隆抗体。本申请的中心假设是，用高甘露糖聚糖高度糖基化的重组Env免疫-类似于HIV-1病毒体上存在的糖型-可以诱导聚糖依赖性中和抗体，其中一个子集在bnAb谱系中。本申请的目的是确定这些新型Env诱导的血浆抗Env聚糖抗体的开发和抗HIV-1功能。因此，在目的1中，将产生针对聚糖依赖性HIV-1包膜表位的现有和新的重组血液记忆B细胞抗体，并表征其抗HIV-1活性。在目标2中，我们将分析疫苗诱导的抗聚糖抗体的个体发育，包括重组mAb生产、谱系成员的计算推断和下一代VHDJH测序。最后，在目标3中，我们将在用抗原性稳定的CON-S gp 140三聚体免疫后，在次级淋巴器官和粘膜组织中询问疫苗诱导的HIV-1 Env聚糖抗体库。这些研究的结果将是我们努力了解包含bnAb表位的HIV-1包膜聚糖免疫原性的重要一步。本文表征的抗体将为免疫原的B细胞谱系设计提供模板，所述免疫原增强恒河猴和人中由Env疫苗接种诱导的聚糖依赖性抗体谱系。

 DESCRIPTION (provided by applicant): The human immunodeficiency virus type 1 (HIV-1) pandemic continues to spread in the absence of a preventative vaccine. Broadly neutralizing antibodies (bnAbs) against HIV-1 can prevent infection of nonhuman primates, but have thus far not been elicited by vaccination. The HIV-1 envelope is covered by a dense array of host glycans that, if recognized by vaccine-induced antibodies, could generate bnAbs. BnAbs with these specificities arise in natural infection. However, to date, vaccine strategies for eliciting anti-Env glycan antibodies have shown glycan-dependent epitopes to be poorly immunogenic. In my studies of rhesus macaques vaccinated with a group M consensus envelope, CON-S, that contains a substantial proportion of high mannose sugars, I have identified macaque plasma antibodies that block the binding of anti-glycan bnAbs to HIV-1 Env. CON-S Env gp140-immunized macaques also possess sufficient antibody titers for detection of direct glycan binding in their plasma, and I have been successful in isolating glycan-reactive rhesus monoclonal antibodies from CON-S Env-vaccinated animals. The central hypothesis of this application is that immunization with a recombinant Env that is heavily glycosylated with high mannose glycans--similar to the glycoforms present on HIV-1 virions--can induce glycan-dependent neutralizing antibodies, a subset of which are in bnAb lineages. The objectives of this application are to define the development and anti-HIV-1 functions of these novel Env-induced plasma anti-Env glycan antibodies. Thus, in Aim 1, existing and new recombinant blood memory B cell antibodies directed to glycan-dependent HIV-1 envelope epitopes will be produced and their anti-HIV-1 activity characterized. In Aim 2, we will profile the ontogeny of vaccine-induced anti-glycan antibodies both with recombinant mAb production, computational inference of lineage members, and next-generation VHDJH sequencing. Finally, in Aim 3, we will interrogate the vaccine-induced HIV-1 Env glycan antibody repertoire in secondary lymphoid organs and mucosal tissue after immunization with antigenic, stabilized CON-S gp140 trimers. The results from these studies will be a major step forward in our effort to understand the immunogenicity of HIV-1 envelope glycans that comprise bnAb epitopes. The antibodies characterized here will provide templates for B cell lineage design of immunogens that enhance the glycan-dependent antibody lineages induced by Env vaccination in rhesus macaques and humans.