Developing Immunogens to Elicit Broadly Neutralizing anti-HIV-1 Antibodies

开发免疫原以引发广泛中和抗 HIV-1 抗体

基本信息

批准号：
10307758
负责人：
Pamela J Bjorkman
金额：
$ 265.41万
依托单位：
CALIFORNIA INSTITUTE OF TECHNOLOGY
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-02-10 至 2023-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10307758
关键词：
AIDS/HIV problem Abbreviations Adjuvant Affinity Animal Model Antibodies Antibody Response Antigens Autologous B cell repertoire B-Cell Antigen Receptor Binding Binding Sites Biochemical Biological Assay Blood Circulation Cells Characteristics Collaborations Complementarity Determining Regions Complex Core Facility Cryoelectron Microscopy Crystallization Development Epitopes Evaluation Frequencies Genes Genetic Engineering Glycine Goals HIV HIV Envelope Protein gp120 HIV vaccine HIV-1 HIV-1 vaccine Human Immunization Immunoglobulin Somatic Hypermutation Immunoglobulins In Vitro Individual Infection Infection prevention Knock-in Knock-in Mouse Knowledge Laboratories Length Leukapheresis Libraries Light Macaca Membrane Methods Mucous Membrane Mus Mutate Persons Polysaccharides Property Proteins Protocols documentation Public Health Publishing Regimen Reporting Research Personnel Sampling Scheme Screening Result Serum Sorting - Cell Movement Structure Testing V3 Loop Vaccination Vaccines Variant Viral Virus Wild Type Mouse Work Yeasts anti-PD1 antibodies base design efficacy evaluation experimental study follow-up gp160 immunogenicity improved in vivo evaluation mimetics neutralizing antibody nonhuman primate pre-clinical prevent protein expression protein protein interaction rare variant rational design receptor binding screening success vaccine access vaccine trial

AIDS/HIV problem Abbreviations Adjuvant Affinity Animal Model Antibodies Antibody Response Antigens Autologous B cell repertoire B-Cell Antigen Receptor Binding Binding Sites Biochemical Biological Assay Blood Circulation Cells Characteristics Collaborations Complementarity Determining Regions Complex Core Facility Cryoelectron Microscopy Crystallization Development Epitopes Evaluation Frequencies Genes Genetic Engineering Glycine Goals HIV HIV Envelope Protein gp120 HIV vaccine HIV-1 HIV-1 vaccine Human Immunization Immunoglobulin Somatic Hypermutation Immunoglobulins In Vitro Individual Infection Infection prevention Knock-in Knock-in Mouse Knowledge Laboratories Length Leukapheresis Libraries Light Macaca Membrane Methods Mucous Membrane Mus Mutate Persons Polysaccharides Property Proteins Protocols documentation Public Health Publishing Regimen Reporting Research Personnel Sampling Scheme Screening Result Serum Sorting - Cell Movement Structure Testing V3 Loop Vaccination Vaccines Variant Viral Virus Wild Type Mouse Work Yeasts anti-PD1 antibodies base design efficacy evaluation experimental study follow-up gp160 immunogenicity improved in vivo evaluation mimetics neutralizing antibody nonhuman primate pre-clinical prevent protein expression protein protein interaction rare variant rational design receptor binding screening success vaccine access vaccine trial

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项目摘要

UNAIDS has documented millions of new HIV-1 infections every year, thus a vaccine for HIV-1 is highly desirable. To date, despite numerous efforts, no immunization regimen reproducibly elicits broadly neutralizing antibodies (bNAbs) against HIV-1. Recently available native-like HIV-1 envelope spike (Env) trimers elicit antibodies that neutralize autologous tier-2 viruses but these antibodies have only limited potency and breadth. The observations that inferred germline (iGL) antibody precursors of bNAbs do not generally bind HIV-1 Env proteins or neutralizing HIV-1 suggested that rationally designed iGL-targeting Env immunogens would be required to initiate bNAb responses. Drs. Bjorkman and Nussenzweig propose a highly collaborative project to apply this approach to target epitopes of two classes of HIV-1 bNAbs: a class related to PGT121 that binds to the base of the V3 variable loop and interacts with the N332gp120 glycan (V3/N332 bNAbs), and IOMA-like bNAbs, a new class of CD4-mimetic CD4 binding site (CD4bs) bNAbs derived from the VH1-2 germline gene segment. The V3/N332 and IOMA classes were chosen because (i) V3/N332 Abs are among the most potent of bNAbs and are commonly found in HIV-infected individuals who develop bNAbs, (ii) IOMA's relatively low number of somatic hypermutations and its normal-length CDRL3 suggest it may be more easily elicited than VRC01-class VH1-2–derived CD4bs bNAbs that are heavily somatically mutated and contain rare 5-residue CDRL3s, and (iii) immunogen design will be facilitated the crystal structure of a natively-glycosylated Env trimer bound to the V3/N332 bNAb 10-1074 and to IOMA. The Bjorkman lab will create immunogens to target iGLs and shepherd bNAb maturation, while the Nussenzweig lab develops immunization schemes to elicit bNAbs using the designed immunogens. The Nussenzweig lab specific aims are: (1) Develop and simplify immunization protocols that elicit bNAbs to V3/N332 in iGL knock-in mice, (2) Adapt immunization protocols developed for V3/N332 bNAbs in knock-in mice to wild type and AlivaMab mice that carry un-rearranged human antibody loci, (3) Develop an immunization protocol to elicit IOMA-like antibodies, and (4) Determine the frequency of IOMA and V3/N332 bNAb precursors in the naïve B cell repertoire of un-infected human donors. The Bjorkman lab specific aims are: (1) Solve structures of iGL–immunogen complexes to aid in structure-based immunogen design, (2) Use structure-based design and library screening to identify Env trimers that bind V3/N332 iGLs with high affinity, (3) Use structural information to guide construction of a yeast display library to find rare variants that bind IOMA iGL, (4) Combine results to create Env trimer immunogens that bind iGLs of both bNAbs and work with Dr. Nussenzweig to evaluate double and single immunogens in mice. These efforts will be supported by Core A (Automated cell/biochemical assays) and Core B (Protein Expression). The proposed experiments will produce candidate immunogens testing in macaques by collaborator Dr. Malcolm Martin and for vaccine trials in humans.

UNAIDS每年都记录了数百万个新的HIV-1感染，因此HIV-1的疫苗很高理想。迄今为止，许多努力，没有可重复引起的免疫方案广泛中和针对HIV-1的抗体（BNABS）。最近可用的类似于本机的HIV-1信封尖峰（ENV）Trimers引起中和自体2病毒但这些抗体的抗体仅具有有限的效力和广度。 BNAB的推断种系（IGL）抗体前体的观察结果通常不结合HIV-1 Env 蛋白质或中和HIV-1表明，理性设计的Igl靶向ENV免疫原会为启动BNAB响应所需。博士。 Bjorkman和Nussenzweig提案一个高度协作的项目将此方法应用于两类HIV-1 BNAB的靶向鉴定：与PGT121相关的类到V3变量循环的底部，并与N332GP120 Glycan（V3/N332 BNABS）和IOMA样相互作用 BNABS，一种新的CD4模拟CD4结合位点（CD4BS）BNAB，衍生自VH1-2种系基因部分。选择V3/N332和IOMA类是因为（I）V3/N332 ABS是最有效的 bnabs，通常在艾滋病毒感染的个体中发现，（ii）ioma相对较低躯体高压及其正常长度的CDRL3的数量表明，它可能更容易引起 VRC01级VH1-2衍生的CD4BS bnabs，它们在体外严重突变，含有稀有的5-残留物 CDRL3S和（iii）免疫原设计将准备属于糖基化Env的晶体结构将Trimer绑定到V3/N332 BNAB 10-1074和IOMA。 Bjorkman实验室将创建免疫原靶 IGLS和Shepherd BNAB成熟，而Nussenzweig Lab Developments免疫方案以引发使用设计的免疫原子的BNAB。 Nussenzweig Lab的特定目的是：（1）开发和简化在Igl敲门小鼠中引起BNAB的V3/N332的免疫协议，（2）适应免疫协议为野生型小鼠和载有未重新编织的野生型小鼠的v3/n332 bnabs开发人抗体局部，（3）开发一种免疫抑制方案以引起类似Ioma的抗体，（4）确定未感染人类的幼稚B细胞库中Ioma和V3/N332 BNAB前体的频率捐助者。 Bjorkman实验室的特定目的是：（1）求解Igl-免疫原子络合物的结构以帮助基于结构的免疫原设计，（2）使用基于结构的设计和库筛选来识别Env 将V3/N332 IGL与高亲和力结合的三聚体，（3）使用结构信息来指导酵母的构造显示库以查找结合ioma Igl的稀有变体，（4）结合结果以创建ENV Trimer免疫原子结合bnabs的IgL，并与Nussenzweig博士一起评估双重和单一免疫原分老鼠。这些努力将由Core A（自动细胞/生化测定）和Core B（蛋白质）支持表达）。提出的实验将在猕猴中产生候选免疫原子测试合作者马尔科姆·马丁（Malcolm Martin）博士和人类的疫苗试验。