A humanized mouse model for vaginal HIV-1 transmission.

用于阴道 HIV-1 传播的人源化小鼠模型。

基本信息

批准号：
10472658
负责人：
LIANG SHAN
金额：
$ 19.69万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-08-20 至 2024-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10472658
关键词：
AIDS prevention Acute Animal Model Anti-Retroviral Agents Autologous BLT mice Blood Cells Bone Marrow CD34 gene CD4 Positive T Lymphocytes CD8-Positive T-Lymphocytes CSF1 gene Cell physiology Cells Chronic Phase Code Development Engraftment Exposure to Female Female genitalia Fetal Liver Genes Goals HIV HIV Infections HIV-1 Hematopoiesis Hematopoietic stem cells Human IL3 Gene Immune Immune response Immune system Immunity Immunodeficient Mouse Implant Inbred BALB C Mice Individual Infection Interleukin-15 Interleukin-6 Investigation Kidney Knock-in Liver Lymphocyte Lymphoid Cell Modeling Mouse Strains Mucosal Immune Responses Mucous Membrane Mus Myelogenous Myeloid Cells Myelopoiesis Names PTPRC gene Patients Pharmaceutical Preparations Prevention Reporting Research Rest System T cell response T-Lymphocyte Testing Thymic Tissue Thymus Gland Tissues Transplantation Umbilical Cord Blood Vaccines Vagina Viral Viral reservoir Virus Diseases acute infection antiretroviral therapy base capsule chronic infection cytokine fetal graft vs host disease hematopoietic stem cell expansion humanized mouse improved insight macrophage memory CD4 T lymphocyte mouse model nonhuman primate pre-exposure prophylaxis prevent progenitor reconstitution reproductive tract tool transmission process vaccine development vaccine efficacy

项目摘要

Abstract Animal models such as small non-human primates and humanized immune system mice (humanized mice) are valuable tools to study HIV prevention by antiretroviral drugs or vaccines. The human bone marrow-liver-thymus (BLT) mouse model allows reconstitution of human lymphoid cells in gut and female reproductive tract (FRT), which makes humanized BLT mice suitable for the studies of HIV mucosal transmission and pre-exposure prophylaxis. To generate humanized BLT mice, human fetal liver and thymus tissue are implanted under the kidney capsule of aforementioned immunodeficient mice engrafted with autologous human HSPCs. The major limitations of the BLT model are: 1) it requires fetal derived human cells and tissues; 2) it develops graft-versus-host disease. Therefore, it is important to develop humanized mouse models that utilize non-fetal derived human HSPCs to reconstitute mucosal human immune system and are susceptible to mucosal HIV transmission. We have developed humanized mouse models that reconstituted human lymphocytes and myeloid cells in the female reproductive tract (FRT), which allowed robust HIV-1 infection through vaginal exposure. Using this mouse model, we propose to investigate: 1) Propagation and dissemination of infection after vaginal exposure to HIV-1; 2) mucosal viral reservoirs in mice treated with antiretroviral drugs; 3) Viral-specific CD8+ T cells in the FRT of HIV-infected mice. Our proposed study will develop a non-fetal derived humanized mouse model that allows robust reconstitution of mucosal human immune cells in the FRT to support vaginal HIV-1 transmission. In addition, it will help us gain a better insight into the human immune responses in the FRT, which will provide implications to the T-cell based vaccine development.

抽象的小型非人灵长类动物和人源化免疫系统小鼠等动物模型（人源化小鼠）是研究抗逆转录病毒药物或疫苗预防艾滋病毒的宝贵工具。人骨髓-肝-胸腺 (BLT) 小鼠模型可重建人骨髓-肝-胸腺 (BLT) 小鼠模型肠道和女性生殖道 (FRT) 中的淋巴细胞，使 BLT 小鼠人源化适用于HIV粘膜传播和暴露前预防的研究。生成人源化BLT小鼠，人胎肝脏和胸腺组织植入肾囊下移植了自体人类 HSPC 的上述免疫缺陷小鼠。主要 BLT模型的局限性是：1）它需要胎儿来源的人体细胞和组织； 2）它发展移植物抗宿主病。因此，开发人源化小鼠模型非常重要利用非胎儿来源的人类 HSPC 来重建人类粘膜免疫系统，易受粘膜HIV传播。我们开发了人性化小鼠模型在女性生殖道（FRT）中重建人类淋巴细胞和骨髓细胞，允许通过阴道暴露进行强烈的 HIV-1 感染。使用该小鼠模型，我们建议调查： 1) 阴道暴露于 HIV-1 后感染的传播和传播； 2）用抗逆转录病毒药物治疗的小鼠的粘膜病毒储库； 3) 病毒特异性 CD8+ T 细胞 HIV感染小鼠的FRT。我们提出的研究将开发一种非胎儿衍生的人源化药物小鼠模型允许在 FRT 中对粘膜人类免疫细胞进行稳健重建支持 HIV-1 阴道传播。此外，它还可以帮助我们更好地了解人类。 FRT 中的免疫反应，这将对基于 T 细胞的疫苗产生影响发展。