HIV-1 vaccine-elicited antibodies target envelope glycans

 描述(申请人提供)：在缺乏预防性疫苗的情况下，人类免疫缺陷病毒1型(HIV-1)大流行继续蔓延。针对HIV-1的广谱中和抗体(BNAbs)可以预防非人灵长类动物的感染，但到目前为止还没有通过疫苗接种而产生。HIV-1包膜被一系列致密的宿主多糖覆盖，如果被疫苗诱导的抗体识别，可能会产生bNAbs。具有这些特异性的bNAb出现在自然感染中。然而，到目前为止，用于诱导抗Env多糖抗体的疫苗策略显示，依赖于多糖的表位免疫原性很差。在我对恒河猴接种M组共识包膜Con-S的研究中，我发现猕猴血浆抗体可以阻断抗糖bNAb与HIV-1env的结合，这种包膜含有相当大比例的高甘露糖。S疫苗gp140免疫的猕猴也具有足够的抗体效价来检测其血浆中的直接多糖结合，我已经成功地从S疫苗免疫的动物中分离到了糖反应性的恒河猴单抗。这一应用的中心假设是，用高度糖基化的重组环境蛋白免疫--类似于HIV-1病毒粒子上的糖形式--可以诱导依赖于糖的中和抗体，其中的一部分在bNab血统中。本申请的目的是确定这些新的Env诱导的血浆抗Env多糖抗体的开发和抗HIV-1功能。因此，在目标1中，将产生针对依赖于糖的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的活性。在目标2中，我们将通过重组mAb的产生、谱系成员的计算推断和下一代VHDJH测序来描述疫苗诱导的抗多糖抗体的个体发育。最后，在目标3中，我们将询问疫苗免疫后次级淋巴器官和粘膜组织中的HIV-1 env多糖抗体库，以及抗原稳定的Con-S gp140三聚体免疫后的情况。这些研究的结果将是我们在努力了解包含bNab表位的HIV-1包膜多糖的免疫原性方面向前迈出的重要一步。这里描述的抗体将为免疫原的B细胞谱系设计提供模板，以增强恒河猴和人类Env疫苗诱导的糖依赖抗体谱系。

 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.