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

项目摘要 由于没有普遍的治愈方法，开发有效的疫苗来预防HIV-1感染仍然是一个主要问题。 目标.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， 可访问的、易处理的和相关的临床前模型系统。艾滋病毒感染、发病机制和 由于HIV的物种特异性嗜性，使用小动物模型的预防受到限制。问世 免疫缺陷小鼠在许多方面具有人类免疫系统（HIS）， 并对HIV相关的翻译研究感兴趣，包括病毒复制，T细胞耗竭， 传播和评估抗逆转录病毒疗法。然而，制定疫苗接种战略的努力 由于适应性免疫应答差和抗原- 免疫后产生特异性抗体。因此，非常需要在HIS小鼠中取得进展， 促进疫苗介导的抗体发展到容易翻译到人类的特定表位。我们 假设在HIS小鼠中通过人抗原呈递细胞增强人T细胞功能和引发 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。本 最后，我们建立了一种表达人类白细胞抗原（HLA）-DQ和HLA-A的新型HIS小鼠品系 在不存在鼠主要组织相容性复合体（MHC）I/II的情况下（以确保在一个细胞上的人T细胞选择）， 小鼠胸腺中更合适的分子）与敲入鼠体内的人CSF 1组合 Csf 1基因座。根据我们小组和其他人发表的数据，我们预计，这种新菌株将支持 改善的T细胞发育/功能以及具有增加的能力的人骨髓细胞的发育 在免疫后引发人类T细胞，并促进HIV-1特异性抗体的产生。我们将利用 这一新的翻译HIS平台：i）确定人类适应性免疫反应的范围， ii）确定中和能力，定义靶向的Env表位，和 描绘针对HIV-1免疫的人适应性免疫应答的序列特征，和iii） 评估一种新的疫苗接种策略，使用针对广泛中和抗体的优化多价免疫原 （bNAb）诱导。总之，这些结果将为这种先进的HIS模型的实用性提供重要的见解 评估能够产生bNAb的HIV-1疫苗接种策略的系统， 在人体临床试验中得到验证。

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.