HIV sexual transmission in mice:study of microbicide efficacy

HIV在小鼠中的性传播：杀菌剂功效的研究

• 批准号: 8318571
• 负责人: MARY Jane POTASH
• 金额: $ 39.82万
• 依托单位: ST. LUKE'S-ROOSEVELT INST FOR HLTH SCIS
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-01 至 2014-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8318571
• 关键词: Accounting; Achievement; Acquired Immunodeficiency Syndrome; Address; Affect; Animal Model; Anti-Retroviral Agents; Area; Award; Cells; Clinical Trials; Communities; Complement; Confocal Microscopy; DNA; DNA Vaccines; Defect; Dendritic Cells; Dependence; Development; Dose; Engineering; Epidemic; Evaluation; Female; Flow Cytometry; Fluorescence; Foundations; Gagging; Goals; HIV; HIV-1; Immune response; Immunity; Immunization; Immunocompetent; Infection; Injection of therapeutic agent; Intervention; Link; Lymphocyte; Measurement; Measures; Modeling; Mus; Mutant Strains Mice; Nucleocapsid; Organ; Partner in relationship; Peptide Hydrolases; Pharmaceutical Preparations; Plasma Cells; Preclinical Testing; Predisposition; Prevention; Prophylactic treatment; Proteins; Public Health; RNA-Directed DNA Polymerase; Relative (related person); Reporting; Research; Resolution; Reverse Transcriptase Inhibitors; Risk; Route; Seminal fluid; Sexual Transmission; System; Systemic infection; T-Lymphocyte; Testing; Time; Tissues; Vaccinated; Vaccination; Vaccines; Vas deferens structure; Viral; Virion; Virus; Virus Diseases; Woman; base; cell type; design; efficacy testing; inhibitor/antagonist; innovation; macrophage; male; man; microbicide; pandemic disease; prevent; reproductive; resistance mutation; response; therapy design; tissue tropism; transmission process

DESCRIPTION (provided by applicant): This application is submitted in response to RFA-AI-07-034. We have constructed a model of systemic infection of immunocompetent mice by chimeric HIV-1, EcoHIV. Our previous studies indicate that EcoHIV replicates in lymphocytes and macrophages in infected mice, infection in mice is sensitive to antiretroviral drugs, productive infection persists for months inducing immune responses, and HIV-1 DNA vaccination can block infection in mice. Preliminary results reported here show that sexual transmission of EcoHIV in mice is rapid and efficient. Our overall goal in this application is to develop the mouse infection system to investigate the mechanisms of sexual transmission of HIV-1 as a platform to test efficacy of candidate microbicides. The Specific Aims of are: 1) to optimize conditions for sexual transmission of EcoHIV in mice and evaluation of interventions. 2) to identify the cell types involved in sexual transmission of EcoHIV. 3) to test the inhibition of sexual transmission of EcoHIV by antiretroviral-based microbicides. 4) to determine the HIV-1 subtype dependence of sexual transmission and efficacy of antiretroviral based microbicides against different HIV-1 subtypes. 5) to determine whether combination administration of an HIV-1 DNA vaccine followed by a microbicide can prevent sexual transmission of subtype B EcoHIV. Chimeric HIV-1 will be transmitted to conventional, immunocompetent female mice by mating with males infected through inoculation. Virus burden in multiple organs will be measured by real- time PCR and productively infected cells will be identified by flow cytometry and confocal microscopy. Accomplishment of Aims 1-3 will provide a firm foundation for and justification to extend the model to Aims 4-5 in studies directly relevant to the current HIV-1 epidemic and realistic means to control it. HIV-1 infection continues to spread worldwide, primarily by sexual transmission. The public health community responded to this pandemic by research into microbicides, compounds that women can apply to prevent transmission of HIV-1 during intercourse. Unfortunately, there is no simple way to determine which of many microbicides being developed actually blocks HIV-1 transmission before women begin their use. Some of the first to be tested by women in clinical trial actually increased HIV-1 transmission. This application is designed to develop a system for preclinical testing of microbicides in mice to determine their ability to reduce or prevent sexual transmission of HIV-1. We have shown that a form of HIV-1 that we genetically engineered to infect mice is very easily transmitted during mating. We propose to optimize this system to determine how well microbicides block sexual transmission of HIV-1. We shall also test in mice how the forms of HIV-1 that are widely distributed today can be controlled by microbicides. We have already shown that vaccination can reduce susceptibility to HIV-1 in mice. We also plan to both vaccinate mice and then treat with microbicides to determine if it is possible to completely prevent sexual transmission of the virus. Our hope is that the model of sexual transmission of HIV-1 in mice can accelerate the development of safe and effective microbicides that can be used to control the AIDS pandemic.

描述（由申请人提供）：此申请是根据RFA-AI-07-034提交的。我们通过嵌合HIV-1（Ecohiv）构建了一种免疫能力小鼠的全身感染模型。我们先前的研究表明，在感染小鼠中的淋巴细胞和巨噬细胞中的生态IV复制，小鼠的感染对抗逆转录病毒药物敏感，生产性感染持续数月以诱导免疫反应，而HIV-1 DNA疫苗接种可以阻止小鼠的感染。此处报告的初步结果表明，ECOHIV在小鼠中的性传播是快速有效的。我们在此应用中的总体目标是开发小鼠感染系统，以研究HIV-1的性传播的机制，作为测试候选微生物疗效的平台。具体目的是：1）优化小鼠中生态传播的条件并评估干预措施。 2）确定与性传播有关的细胞类型。 3）测试通过基于抗逆转录病毒的微生物抑制ECOHIV的性传播。 4）确定抗逆转录病毒对不同HIV-1亚型的性传播和疗效的HIV-1亚型依赖性。 5）确定施用HIV-1 DNA疫苗，然后是菌心的组合可以防止亚型B EcoHIV的性传播。嵌合HIV-1通过与通过接种感染的男性交配，将嵌合HIV-1传播到常规的免疫能力小鼠。多个器官中的病毒负担将通过实时PCR进行测量，并通过流式细胞仪和共聚焦显微镜来鉴定感染的细胞。目标1-3的实现将为与当前的HIV-1流行病和现实手段直接相关的研究中的目标4-5提供牢固的基础和理由。 HIV-1感染继续在全球范围内传播，主要是通过性传播传播。公共卫生界通过对生身分的研究来回应这一大流行，妇女可以申请以防止在性交期间申请HIV-1的传播。不幸的是，没有简单的方法来确定哪些开发的许多微生物实际上会在女性开始使用之前阻止HIV-1传播。在临床试验中，女性首先要测试的一些人实际上增加了HIV-1的传播。该应用旨在开发一种用于小鼠临床前测试的系统，以确定其降低或防止HIV-1性传播的能力。我们已经表明，在交配过程中，我们在基因上为感染小鼠进行基因工程的一种HIV-1形式很容易传播。我们建议优化该系统，以确定微生物层如何阻止HIV-1的性传播。我们还将在小鼠中测试当今分布广泛分布的HIV-1形式如何通过菌心来控制。我们已经表明，疫苗接种可以减少小鼠对HIV-1的敏感性。我们还计划对小鼠进行疫苗接种，然后用微生物治疗，以确定是否有可能完全防止病毒的性传播。我们的希望是，在小鼠中，HIV-1的性传播模型可以加速可用于控制艾滋病大流行的安全有效杀菌剂的发展。