Murine Model of Sexually Transmitted Disease-enhanced HIV Transmission

性传播疾病增强艾滋病毒传播的小鼠模型

• 批准号: 7347566
• 负责人: GREGORY T SPEAR
• 金额: $ 21.78万
• 依托单位: RUSH UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-02-01 至 2009-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7347566
• 关键词: Acute; Affect; Animal Model; Appearance; Applications Grants; Biohazardous Substance; CCR5 gene; Cells; DNA; Data; Detection; Dose; Fluorescence; Goals; Grant; HIV; HIV Infections; Human; Human Herpesvirus 2; Immunity; In Vitro; Infection; Literature; Lymphoid Tissue; Measures; Mediating; Modeling; Mus; Personal Satisfaction; Phenotype; Polymerase Chain Reaction; Population; Predisposition; Proteins; Research; Sexual Transmission; Sexually Transmitted Diseases; Spleen; Testing; Time; Transgenic Mice; Vagina; Virus; Woman; concept; cyclin T1; env Gene Products; in vivo; innovation; lymph nodes; microbicide; prevent; research study; trafficking; transmission process

DESCRIPTION (provided by applicant): The presence of sexually transmitted diseases (STDs) in women increases susceptibility to sexual transmission of HIV and over 300 million people worldwide are estimated to have STDs. The long-term goal of our research is to develop an animal model of HIV vaginal infection and use it to study how STDs increase susceptibility to HIV infection. The model will also be useful for evaluating the efficacy of microbicides in preventing HIV infection as well as studies of mucosal anti-HIV immunity. The specific goals of this innovation grant application are to develop a murine HIV vaginal infection model using mice transgenic (Tg) for human CD4, CCR5 and cyclin T1 and use the model to determine if a pre-existing infection by herpes simplex virus type-2 (HSV-2) increases susceptibility to subsequent infection by HIV. HSV-2 is an especially appropriate STD to study because it is well-documented to increase susceptibility to HIV infection and it is highly prevalent. In addition, there is an extensive supportive literature on HSV-2 vaginal infection in mice. This proof-of-concept study will establish if the Tg mice can be used as a model for sexual transmission of HIV and if HSV-2 pre-infection increases HIV infection in this model. Mice will be infected with HIV capable of only a single round of infection, which has the advantages of facilitating identification of the initial targets of HIV infection and providing a substantially reduced biohazard. HIV infection will be measured by detection of HIV DNA and appearance of green fluorescence protein-positive cells. In Aim 1 we will determine if intravaginal infection of Tg mice with HIV results in detectable HIV infection and if a pre-existing HSV-2 infection, either acute or latent, affects susceptibility to HIV infection. In Aim 2, we will determine the effect of HSV-2 infection on the trafficking of HIV-infected cells to lymphoid tissue and the replication state and phenotype of HIV-infected cells. This revised application includes new data that shows infection of Tg mice by HIV can be detected both in vitro and in vivo thus indicating the feasibility of the proposed experiments.

描述（由申请人提供）：妇女中存在性传播疾病（STD）的存在会增加对艾滋病毒性传播的敏感性和全球超过3亿人的易感性。我们研究的长期目标是开发一种HIV阴道感染的动物模型，并利用它来研究性病如何增加对HIV感染的敏感性。该模型也将有助于评估微生物在预防HIV感染以及粘膜抗HIV免疫的研究中的功效。该创新赠款应用的具体目标是使用人类CD4，CCR5和Cyclin T1的小鼠转基因（TG）开发鼠类HIV阴道感染模型，并使用该模型来确定疱疹病毒类型-2（HSV-2）是否曾先前感染了HSV的感染是否会增加HIV的易感性。 HSV-2是一个特别适合研究的性病，因为它有充分的文献记录，可以增加对HIV感染的敏感性，并且非常普遍。此外，关于小鼠HSV-2阴道感染的大量支持文献。这项概念验证研究将确定TG小鼠是否可以用作HIV性传播的模型，以及HSV-2的感染前是否会增加该模型中的HIV感染。小鼠将只能感染一轮感染的艾滋病毒，这具有促进鉴定艾滋病毒感染的初始靶标并提供大幅降低的生物危害的优势。 HIV感染将通过检测HIV DNA和绿色荧光蛋白阳性细胞的外观来测量。在AIM 1中，我们将确定患有HIV的TG小鼠的阴道内感染是否会导致可检测的HIV感染，以及急性或潜在的先前存在的HSV-2感染是否会影响对HIV感染的易感性。在AIM 2中，我们将确定HSV-2感染对HIV感染细胞对淋巴组织的运输以及HIV感染细胞的复制状态和表型的影响。该修订后的应用包括新数据，可以在体外和体内检测到通过HIV感染HIV的感染，从而表明了所提出的实验的可行性。