Vaginal/Rectal HIV Transmission Model

阴道/直肠 HIV 传播模型

• 批准号: 7884349
• 负责人: J. Victor Garcia-Martinez
• 金额: $ 56.47万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-08-01 至 2013-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7884349
• 关键词: Animal Model; Antibodies; Antiviral Agents; Autologous; Bone Marrow Transplantation; CCR5 gene; CD4 Positive T Lymphocytes; CXCR4 gene; Cells; Clinical Data; Clinical Trials; Complement; Data; Development; Effectiveness; Evaluation; Fetal Liver; Future; Goals; Grant; HIV; HIV-1; Hematopoietic; Hematopoietic System; Heterosexuals; Human; Immunodeficient Mouse; Implant; In Situ Hybridization; Infection; Laboratories; Local Microbicides; Macaca; Mesentery; Mind; Modeling; Mus; Organoids; Plasma; Predisposition; Preventive Intervention; Prophylactic treatment; Research Personnel; Role; SIV; Seminal fluid; Small Intestines; Spleen; System; Systemic infection; T-Cell Depletion; Testing; Thymic Tissue; Tropism; Vagina; Viral; Virus; Virus Diseases; Virus Replication; Woman; base; hematopoietic tissue; human stem cells; inhibitor/antagonist; interest; lymph nodes; microbicide; novel; novel strategies; peripheral blood; pre-clinical; preclinical evaluation; prevent; programs; receptor; reconstitution; rectal; research study; transmission process

DESCRIPTION (provided by applicant): The long term-goal of our laboratory is to investigate novel approaches to prevent HIV transmission by the use of antivirals and microbicides. For this purpose we have developed and implemented a novel small animal model where human stem cells are used to reconstitute the hematopoietic system of immunodeficient mice. In these humanized mice (designated BLT to represent the fact they are generated from a bone marrow transplant of mice previously implanted with a piece of autologous human fetal liver and thymic tissue) there is systemic reconstitution with human hematopoietic cells in all hematopoietic and non-hematopoietic tissues tested. As shown in the Preliminary Results section of this grant, these humanized mice are susceptible to intrarectal and intravaginal infection with X4- and R5-Tropic HIV-1. Infection results in plasma antigenemia, progressive depletion of human CD4+ cells from the peripheral blood and the development of HIV-1 specific human antibodies. In addition, our data show that human CD4 T cell depletion is systemic and most dramatic in the human thymic organoid. Using in situ hybridization we demonstrate systemic infection by showing the presence of infected cells in the large and small intestine, mesenteric lymph nodes, spleen, and thymic organoid. In this grant we propose to expand on these remarkable results and to establish the suitability of this system to evaluate pre-exposure prophylaxis of HIV transmission and by antivirals and/or microbicides. With this in mind we propose the following Specific Aims: Specific Aim 1) To characterize the role of co-receptor tropism in the infection of BLT mice after intrarectal inoculation. Specific Aim 2) To evaluate the efficacy of topical and systemic administration of antivirals to prevent intrarectal HIV-1 infection of BLT mice. Specific Aim 3) To evaluate the susceptibility BLT mice to intravaginal infection with HIV-1. Specific Aim 4). To determine the efficiency of topical and systemic antivirals to prevent intravaginal HIV transmission. By establishing these basic parameters we will determine the potential utility of this novel system to provide important pre-clinical data to serve as the possible basis for the future implementation of clinical trials.

描述（由申请人提供）：我们实验室的长期目标是研究通过使用抗病毒药和杀菌剂来防止HIV传播的新方法。为此，我们开发了一种新型的小动物模型，其中人类干细胞用于重建免疫缺陷小鼠的造血系统。在这些人源化的小鼠中（指定的BLT表示它们是由先前用自体胎儿肝脏和百里香组织植入的小鼠的骨髓移植产生的），在所有造血和非肾小球组织中，都有人类造血细胞的全身性重构。如本赠款的初步结果部分所示，这些人源化的小鼠容易受到直肠内和阴道内感染的X4-和R5-热带HIV-1。感染会导致血浆抗血症，从外周血逐渐消耗人CD4+细胞以及HIV-1特异性人类抗体的发展。此外，我们的数据表明，人CD4 T细胞的耗竭是全身性，并且在人胸腺类器官中是最引人注目的。使用原位杂交我们通过在大肠和小肠，肠系膜淋巴结，脾和胸腺器官中表现出感染细胞的存在来证明全身感染。在这笔赠款中，我们建议扩展这些显着的结果，并确定该系统以评估艾滋病毒传播和抗病毒药和/或杀菌剂的预防预防的适用性。考虑到这一点，我们提出了以下特定目的：具体目的1）表征共接到直肠内接种后联合受体tropism的作用在BLT小鼠感染中的作用。具体目的2）评估局部和全身施用抗病毒药的功效，以防止直肠内HIV-1感染BLT小鼠。具体目标3）评估对HIV-1的易感性BLT小鼠的敏感性。特定目标4）。确定局部和全身性抗病毒药的效率，以防止阴道发生HIV传播。通过建立这些基本参数，我们将确定这种新型系统的潜在效用，以提供重要的临床前数据，以作为未来实施临床试验的可能基础。