Project 1: Immunization strategies to elicit broadly neutralizing antibodies against HIV-1

项目1.诱导抗HIV-1bNAb的免疫战略PI：Bjorkman，P.J./Nussenzweig，M.C. 好了！ 摘要 艾滋病是一种可以预防的疾病，然而，根据联合国艾滋病规划署的说法，数百万人是新感染的 每年都有。因此，设计艾滋病毒-1疫苗是非常可取的。迄今为止，尽管作出了许多努力， 没有一种免疫方案可以重复地产生针对HIV-1的广谱中和抗体(BNAbs)。最近 现有的类似天然环境的三聚体确实能诱导抗体中和自体第二层病毒，但这些 抗体的效力和广度有限。观察到大多数类似天然的包膜蛋白具有 不结合bNAbs推测的生殖系(IGL)抗体前体提示合理设计IGL 需要靶向免疫原才能启动bNAb反应。努森茨韦格实验室已经证实了这一点 靶向V3环碱基的IGL PGT121 bNAb小鼠的敲门假说和 周围的多聚糖(V3/N332)。用IGL靶向蛋白免疫，然后再用一系列更天然的- Look Env三聚体在IGL PGT121 bNAb敲入小鼠中诱导出bNAb。建议的长期目标是 研究将把这些研究扩展到其他更接近人类免疫的动物模型 也可与其他类型的bNAbs反应，例如靶向CD4bs的IOMA样bNAbs。要完成 这些目标努森茨韦格博士将与比约克曼博士合作，设计和测试新的免疫原和 诱导V3/N332和IOMA样bNAb在敲入小鼠、野生型小鼠和 携带未重排的人类免疫球蛋白基因座。Nussenzweig实验室计划：1)优化以前的 旨在诱导类似PGT121的bNAb的免疫方案；2)将该免疫方案的使用范围扩大到 针对V3/N332位点的其他IGL bNAb敲入小鼠，如BG18GL小鼠；3)设计共识 诱导V3/N332 bNAbs类的一系列免疫原；4)设计免疫策略 IOMAGL基因敲除小鼠的Ioma样CD4bs抗体；5)将免疫实验扩展到野生型 小鼠和携带未重排的人类免疫球蛋白基因的小鼠；6)评估新的 从健康捐献者中分离出bNAb前体的免疫原。拟议中的实验将产生 疫苗临床试验的候选免疫原。 好了！

Proj.1 Immunization strategies to elicit bNAbs against HIV-1 PI: Bjorkman, P.J./Nussenzweig, M.C. ! Summary AIDS is a preventable disease, however, according to UNAIDS, millions of people are newly infected every year. The design of a vaccine for HIV-1 is therefore highly desirable. To date, despite numerous efforts, no immunization regimen reproducibly elicits broadly neutralizing antibodies (bNAbs) against HIV-1. Recently available native-like Env trimers do elicit antibodies that neutralize autologous tier-2 viruses but these antibodies have only limited potency and breadth. The observation that most of the native-like Env proteins do not bind the inferred germline (iGL) antibody precursors of bNAbs suggested that rationally designed iGL targeting immunogens would be required to initiate bNAb responses. The Nussenzweig lab has confirmed this hypothesis in knock in mice that carry the iGL PGT121 bNAb which targets the base of the V3 loop and surrounding glycans (V3/N332). Immunization with iGL targeting proteins followed by a series of more native- looking Env trimers elicited bNAbs in iGL PGT121 bNAb knock-in mice. The long term goal of the proposed research is to extend these studies to other animal models that more closely resemble a human immune response and also to other types of bNAbs such as the IOMA-like bNAbs targeting the CD4bs. To accomplish these goals Dr. Nussenzweig will work with Dr. Bjorkman to design and test new immunogens and immunization strategies to elicit V3/N332 and IOMA-like bNAbs in knock-in mice, wild type mice and mice that carry un-rearranged human immunoglobulin loci. The Nussenzweig lab plans to: 1) optimize the previous immunization protocol designed to elicit PGT121-like bNAbs; 2) extend the use of this immunization regimen to other iGL bNAb knock-in mice targeting the V3/N332 site such as the BG18GL mice; 3) design a consensus series of immunogens that elicits the class of V3/N332 bNAbs; 4) design immunization strategies that elicit IOMA-like CD4bs antibodies in IOMAGL knock-in mice; 5) extend these immunization experiments to wild type mice and mice that carry un-rearranged human immunoglobulin loci; 6) evaluate the suitability of the new immunogens to isolate bNAb precursors from healthy donors. The proposed experiments will produce candidate immunogens for vaccine clinical trials. !