Characterizing antibody responses to HIV-1 vaccination in next-generation immune humanized mice

表征下一代免疫人源化小鼠对 HIV-1 疫苗接种的抗体反应

• 批准号: 10673292
• 负责人: Jeremy Allen Goettel
• 金额: $ 72.07万
• 依托单位: VANDERBILT UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-03-21 至 2027-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10673292
• 关键词: Acceleration; Animal Model; Antibodies; Antibody Formation; Antibody Response; Antigen-Presenting Cells; Antigens; Autologous; B-Cell Antigen Receptor; B-Lymphocytes; Basic Science; Binding Sites; Biological Models; CD34 gene; CSF1 gene; Cell Communication; Cell Separation; Cell physiology; Clinical Trials; Complex; Data; Development; Disease; Engraftment; Ensure; Epitopes; Ethics; Evaluation; Exhibits; Future; Generations; Genes; Goals; HIV; HIV Infections; HIV-1; HLA Antigens; Hematopoiesis; Hematopoietic stem cells; Histocompatibility Antigens Class I; Human; Immune; Immune response; Immune system; Immunization; Immunodeficient Mouse; Immunophenotyping; Implant; Individual; Infection; Investigation; Liver; Longevity; Lymphocyte; Lymphoid Cell; Major Histocompatibility Complex; Mediating; Methods; Mouse Strains; Mus; Myelogenous; Myeloid Cells; Myelopoiesis; Natural Killer Cells; Operative Surgical Procedures; Pathogenesis; Penetration; Polysaccharides; Pre-Clinical Model; Prevention; Protocols documentation; Publishing; Research Personnel; Somatic Mutation; Source; System; T-Cell Activation; T-Cell Depletion; T-Cell Development; T-Lymphocyte; Techniques; Testing; Thymus Gland; Tissues; Translating; Translational Research; Tropism; Umbilical Cord Blood; Vaccinated; Vaccination; Vaccines; Virus; Virus Diseases; Virus Replication; Work; Xenograft procedure; activation-induced cytidine deaminase; adaptive immune response; adaptive immunity; antigen-specific T cells; antiretroviral therapy; clinical application; fetal; graft vs host disease; human fetus tissue; humanized mouse; improved; insight; interest; mouse model; nanoparticle; neutralizing antibody; next generation; nonhuman primate; novel; pre-clinical; prevent; receptor binding; reconstitution; response; translational study; transmission process; universal vaccine; vaccination protocol; vaccination strategy; vaccine trial

PROJECT SUMMARY With no universal cure, development of an effective vaccine to prevent HIV-1 infection remains a primary goal. A major hurdle for the development of successful vaccination strategies has been the lack of affordable, accessible, tractable, and relevant preclinical model systems. Investigations on HIV infection, pathogenesis, and prevention using small animal models have been limiting due to the species-specific tropism of HIV. The advent of immunodeficient mice harboring a human immune system (HIS) in many ways has broadened accessibility and interest in HIV-related translational studies including viral replication, T cell depletion, methods of transmission, and evaluation of antiretroviral therapies. Nevertheless, efforts to develop vaccination strategies against HIV in current HIS mice have been thwarted due to poor adaptive immune responses and antigen- specific antibody development following immunization. Thus, there is a great need for advances in HIS mice that promote vaccine-mediated antibody development to specific epitopes that would easily translate to humans. We hypothesize that enhanced human T cell function and priming via human antigen presenting cells in HIS mice will facilitate efficient T/B cell interactions and enable evaluation of vaccination strategies against HIV-1. To this end, we have developed a novel HIS mouse strain expressing human leukocyte antigens (HLA)-DQ and HLA-A in the absence of murine major histocompatibility complex (MHC) I/II (to ensure human T cell selection on a more appropriate molecules in the mouse thymus) in combination with human CSF1 knocked into the murine Csf1 locus. Based on published data from our group and others, this novel strain, we anticipate, will support improved T cell development/function as well as the development of human myeloid cells with increased capacity to prime human T cells following immunization and facilitate HIV-1-specific antibody production. We will leverage this new translational HIS platform to: i) Determine the scope of the human adaptive immune response to infection with HIV-1 R5 virus, ii) Determine the neutralization ability of, define the Env epitopes targeted by, and delineate the sequence features for the human adaptive immune response to HIV-1 immunization, and iii) assess a novel vaccination strategy using optimized multivalent immunogens for broad neutralizing antibodies (bNAb) elicitation. Together, these results will provide critical insights into the utility of this advanced HIS model system to assess HIV-1 vaccination strategies capable of generating bNAbs to accelerate prioritization to validate in human clinical trials.

项目摘要 由于无法普遍治愈，开发有效的疫苗以预防HIV-1感染仍然是主要的 目标。成功开发成功疫苗接种策略的主要障碍是缺乏负担得起的 可访问，可拖动和相关的临床前模型系统。对HIV感染，发病机理和 由于艾滋病毒的物种特异性的向热，使用小动物模型的预防已限制。出现 具有人类免疫系统（HIS）的免疫缺陷小鼠在许多方面都扩大了可及性 对与HIV相关的转化研究的兴趣，包括病毒复制，T细胞耗竭，方法 抗逆转录病毒疗法的传播和评估。然而，制定疫苗接种策略的努力 由于适应性免疫反应和抗原 - 免疫后特定的抗体发育。因此，他的老鼠非常需要进步 促进疫苗介导的抗体开发，以易于转化为人类的特定表位。我们 假设增强了人类T细胞功能并通过他的小鼠中的人类抗原呈现细胞启动 将促进有效的T/B细胞相互作用，并能够评估针对HIV-1的疫苗接种策略。对此 最后，我们开发了一本小说，他的小鼠菌株表达人白细胞抗原（HLA）-DQ和HLA-A-a 在没有鼠的主要组织相容性复合物（MHC）I/II的情况下 小鼠胸腺中更合适的分子与人CSF1结合被击倒到鼠 CSF1基因座。根据我们小组和其他人的发布数据，我们预计这种小说的压力将支持 改善了T细胞的发育/功能以及能力增加的人髓样细胞的发展 免疫后，人类T细胞促进并促进HIV-1特异性抗体产生。我们将利用 这种新的翻译平台为：i）确定人类适应性免疫反应的范围 感染HIV-1 R5病毒，ii）确定定义由和定义的ENV表位的中和能力。 描述人类适应性免疫对HIV-1免疫的序列特征，而III） 使用优化的多价免疫原来评估一种新型的疫苗接种策略，用于广泛中和抗体 （BNAB）启发。这些结果一起将为这一高级模型的实用性提供关键的见解 评估HIV-1疫苗接种策略的系统 在人类临床试验中验证。