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: 8508809
• 负责人: MARY Jane POTASH
• 金额: $ 38.04万
• 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 2015-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8508809
• 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; Epidemic; Evaluation; Female; Flow Cytometry; Fluorescence; Foundations; Gagging; Genetic Engineering; 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）：本申请是根据 RFA-AI-07-034 提交的。我们构建了嵌合HIV-1、EcoHIV对免疫活性小鼠进行全身感染的模型。我们之前的研究表明，EcoHIV 在受感染小鼠的淋巴细胞和巨噬细胞中复制，小鼠的感染对抗逆转录病毒药物敏感，有效感染持续数月，诱导免疫反应，而 HIV-1 DNA 疫苗接种可以阻止小鼠的感染。本文报道的初步结果表明，EcoHIV 在小鼠体内的性传播是快速且有效的。我们在此应用中的总体目标是开发小鼠感染系统来研究 HIV-1 的性传播机制，作为测试候选杀菌剂功效的平台。具体目标是： 1) 优化小鼠体内 EcoHIV 性传播的条件并评估干预措施。 2) 鉴定参与EcoHIV性传播的细胞类型。 3) 测试抗逆转录病毒杀菌剂对 EcoHIV 性传播的抑制作用。 4) 确定性传播的HIV-1亚型依赖性以及基于抗逆转录病毒的杀菌剂针对不同HIV-1亚型的功效。 5) 确定 HIV-1 DNA 疫苗与杀微生物剂的联合施用是否可以预防 B 亚型 EcoHIV 的性传播。嵌合HIV-1将通过与接种感染的雄性小鼠交配而传播给传统的、具有免疫能力的雌性小鼠。将通过实时 PCR 测量多个器官中的病毒负荷，并通过流式细胞术和共聚焦显微镜识别有效感染的细胞。目标 1-3 的实现将为在与当前 HIV-1 流行病直接相关的研究中将该模型扩展到目标 4-5 提供坚实的基础和理由，并提供实际的控制方法。 HIV-1 感染继续在世界范围内传播，主要通过性传播。公共卫生界通过研究杀微生物剂来应对这一流行病，妇女可以使用杀微生物剂来预防性交过程中 HIV-1 的传播。不幸的是，在女性开始使用之前，没有简单的方法可以确定正在开发的多种杀菌剂中的哪一种能够真正阻止 HIV-1 传播。在临床试验中，一些首先由女性进行测试的药物实际上增加了 HIV-1 的传播。该应用旨在开发一种对小鼠进行杀微生物剂临床前测试的系统，以确定其减少或预防 HIV-1 性传播的能力。我们已经证明，我们通过基因工程改造来感染小鼠的一种 HIV-1 在交配过程中很容易传播。我们建议优化该系统，以确定杀菌剂阻止 HIV-1 性传播的效果。我们还将在小鼠身上测试如何通过杀微生物剂来控制当今广泛分布的 HIV-1 形式。我们已经证明，疫苗接种可以降低小鼠对 HIV-1 的易感性。我们还计划给小鼠接种疫苗，然后用杀微生物剂进行治疗，以确定是否有可能完全阻止病毒的性传播。我们希望小鼠体内 HIV-1 的性传播模型能够加速开发安全有效的杀菌剂，用于控制艾滋病的流行。