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

项目总结 在没有万能疗法的情况下，开发有效的疫苗来预防艾滋病毒-1感染仍然是首要任务 进球。制定成功的疫苗接种战略的一个主要障碍是缺乏负担得起的疫苗， 可访问的、易处理的和相关的临床前模型系统。人类免疫缺陷病毒感染、发病机制和 由于HIV的物种特异性取向，使用小动物模型进行预防一直是有限的。《降临》 在许多方面拥有人类免疫系统(HIS)的免疫缺陷小鼠的研究扩大了可获得性 以及对艾滋病毒相关翻译研究的兴趣，包括病毒复制，T细胞耗尽，方法 传播，以及抗逆转录病毒治疗的评估。尽管如此，制定疫苗接种战略的努力 目前在HIS小鼠中对抗HIV的努力已经受挫，因为适应性免疫反应和抗原- 免疫后产生特异性抗体。因此，非常需要在他的小鼠身上取得进展 促进疫苗介导的抗体发展到特定的表位，这些表位很容易转化为人类。我们 在His小鼠体内通过人类抗原提呈细胞增强人类T细胞功能和启动的假说 将促进T/B细胞的有效相互作用，并能够评估针对艾滋病毒-1的疫苗接种战略。对这件事 最后，我们培育了一种新的表达人类白细胞抗原(HLADQ)和HLAA的His小鼠品系 在没有小鼠主要组织相容性复合体(MHC)I/II的情况下(确保人类T细胞在 小鼠胸腺中更合适的分子)与人CSF1共同作用于小鼠 CSF1基因座。根据我们小组和其他人公布的数据，我们预计这种新的毒株将支持 T细胞发育/功能的改善以及人类髓系细胞的发育能力增加 为免疫后的人类T细胞做好准备，促进HIV-1特异性抗体的产生。我们将利用 这个新的翻译HIS平台：i)确定人类适应性免疫反应的范围 感染HIV-1R5病毒，ii)确定其中和能力，确定其靶向的环境表位，以及 描述人类对艾滋病毒-1免疫的适应性免疫反应的序列特征，以及三) 使用针对广谱中和抗体的优化多价免疫原评估一种新的疫苗接种策略 (BNab)启发性。总而言之，这些结果将为这一先进的HIS模型的实用性提供关键的见解 评估能够产生bNAbs的HIV-1疫苗接种战略的系统，以加速确定优先顺序 在人体临床试验中进行验证。

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.