Mechanisms of protective immunity induced by live attenuated SIV vaccines

SIV减毒活疫苗诱导保护性免疫的机制

• 批准号: 7616226
• 负责人: R. PAUL JOHNSON
• 金额: $ 399.02万
• 依托单位: HARVARD MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-04-15 至 2012-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7616226
• 关键词: Mechanisms; protective; immunity; induced; live

DESCRIPTION (provided by applicant): Lack of information on the immunologic mechanisms responsible for protection against HIV infection remains one of the major obstacles to the development of a safe and effective AIDS vaccine. Vaccination of macaques with attenuated SIV strains has consistently proven to be the most effective means to induce protection against pathogenic SIV challenge in macaques. Intensive study of macaques vaccinated with attenuated SIV strains therefore represents one of the best experimental models available for the determination of mechanisms of protective immunity against lentivirus infection. The overall goal of this Program Project application is to undertake a comprehensive, multidisciplinary effort to define mechanisms of immune protection mediated by live attenuated SIV strains. Complementary experiments conducted by three principal investigators with distinct areas of expertise will examine: 1. Mechanisms of mucosal protection induced by attenuated SIV. These experiments will undertake a detailed examination of the evolution of adaptive and innate immune responses induced by SIV?nef and correlate these responses with protection, examine the effect of prolonged B cell depletion on protective immunity, and study viral replication and immune responses in the female reproductive tract of SIV?nef-vaccinated animals after vaginal challenge. 2. The contribution of anti-envelope immune responses to protection mediated by live attenuated SIV. Specific questions include: Does a mismatch of envelope sequences in the challenge virus decrease the degree of protection? Does challenge with a closely-matched SIV strain that differs dramatically in coreceptor usage influence the degree of protection? Does variation in the strength of the anti-envelope antibody response induced using modified single-cycle SIV influence the degree of protection? 3. Mucosal immunity and heterologous protection induced by single-cycle SIV (scSIV). These experiments will examine if the site of immunization with scSIV determines the mucosal homing properties of T cell responses and resistance to an intrarectal challenge with SIVmac239; whether the site of priming influences the ability of virus-specific T cell responses to protect against a vaginal challenge with SIVmac239; and whether immunization with a mixture of antigenically diverse strains of scSIV can broaden virus-specific immune responses and enhance protection against a heterologous challenge with SIVmac239. Results from these studies should shed light on the nature of immune responses able to protect against HIV/SIV infection, which remains one of the outstanding unanswered questions of AIDS vaccine research, and thus will have important implications for the design of clinically applicable AIDS vaccines. PROJECT 1: Mechanisms of mucosal protection induced by attenuated SIV (Johnson, R. Paul) PROJECT 1 DESCRIPTION (provided by applicant): Lack of information on mechanisms of protection against HIV/SIV infection remains one of the leading obstacles to the development of a safe and effective AIDS vaccine. Vaccination of macaques with attenuated SIV strains has consistently proved to be the most effective means of inducing protection against pathogenic SIV challenge and offers the best available experimental model to define specific mechanisms responsible for protection. Previous studies from our group have provided evidence that SIV-specific CD8+ T cell and humoral responses both contribute to protective immunity induced by SIV?nef but have not been able to assess their relative importance or the potential contributions of novel adaptive (e.g. CD4+ T effector cells) or innate immune responses to protection. The goal of the current application is to utilize a number of novel techniques to carry out a comprehensive analysis of the role of adaptive and innate immune responses in mediating protection induced by SIV?nef against vaginal challenge, one of the most important modes of HIV transmission. Specific aims include: 1: To examine the evolution of adaptive and innate immune responses induced by SIV?nef and to correlate these responses with protection against homologous and heterologous challenge. 2: To examine the effect of prolonged B cell depletion on protective immunity induced by SIV?nef. 3: To examine viral replication, innate and adaptive immune responses in the female reproductive tract of SIV?nef-vaccinated animals after vaginal challenge.

说明(由申请人提供)：缺乏关于预防艾滋病毒感染的免疫机制的信息，仍然是开发安全有效的艾滋病疫苗的主要障碍之一。用减毒的SIV毒株接种猕猴已被证明是诱导猕猴抵抗病原性SIV攻击的最有效手段。因此，对接种SIV减毒株的猕猴的深入研究是确定慢病毒感染保护性免疫机制的最佳实验模型之一。该计划项目申请的总体目标是开展一项全面的、多学科的努力，以确定由活的减毒SIV毒株介导的免疫保护机制。由三个具有不同专业领域的主要研究人员进行的互补性实验将检验：1.由减毒SIV诱导的粘膜保护机制。这些实验将对SIV？NEF诱导的适应性和先天免疫反应的演变进行详细的研究，并将这些反应与保护相关联，检测长期B细胞耗竭对保护性免疫的影响，以及研究SIV？NEF免疫动物在阴道攻击后雌性生殖道中的病毒复制和免疫反应。2.抗包膜免疫应答在减毒活疫苗免疫保护中的作用。具体问题包括：挑战病毒中的包膜序列不匹配是否会降低保护程度？与SIV毒株紧密匹配、在辅受体使用上存在显著差异的挑战是否会影响保护程度？改良单周期SIV诱导的抗包膜抗体应答强度的变化是否影响保护程度？3.单周期SIV诱导的粘膜免疫和异体保护。这些实验将检查scSIV免疫部位是否决定了T细胞反应的粘膜归巢特性和对SIVmac239直肠内攻击的抵抗力；启动部位是否影响病毒特异性T细胞反应抵御SIVmac239阴道攻击的能力；以及scSIV抗原性不同毒株的混合免疫是否可以扩大病毒特异性免疫反应并增强对SIVmac239异源挑战的保护。这些研究的结果将有助于阐明免疫反应的性质，从而能够预防HIV/SIV感染，这仍然是艾滋病疫苗研究中悬而未决的问题之一，因此将对临床适用的艾滋病疫苗的设计具有重要意义。 项目1：减毒SIV诱导的粘膜保护机制(Johnson，R.Paul) 项目1说明(由申请者提供)：缺乏关于预防艾滋病毒/SIV感染的机制的信息，仍然是开发安全有效的艾滋病疫苗的主要障碍之一。用减毒的SIV毒株接种猕猴已被证明是诱导对致病性SIV攻击的保护最有效的手段，并提供了最好的可用实验模型来确定具体的保护机制。本课题组以前的研究已经提供了证据，表明SIV特异性CD8+T细胞和体液反应都有助于SIV？NEF诱导的保护性免疫，但还不能评估它们的相对重要性或新的适应性(如CD4+T效应细胞)或先天免疫反应对保护的潜在贡献。目前的应用目的是利用一些新技术来全面分析获得性免疫反应和先天免疫反应在SIV？NEF诱导的对阴道攻击的保护中的作用，阴道攻击是HIV最重要的传播方式之一。具体目标包括：1：检测SIV？NEF诱导的适应性和先天免疫反应的演变，并将这些反应与对同源和异源攻击的保护相关联。2.检测B细胞长期耗竭对SIV、NEF诱导的保护性免疫的影响。3.检测SIV-NEF免疫动物经阴道攻击后雌性生殖道内病毒复制、先天免疫和获得性免疫反应。