Mechanisms of protective immunity induced by live attenuated SIV vaccines

描述（由申请人提供）：缺乏关于负责保护免受HIV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SIV毒株接种猕猴一直被证明是在猕猴中诱导针对致病性SIV攻击的保护的最有效手段。因此，对用减毒SIV毒株接种的猕猴的深入研究代表了可用于确定针对慢病毒感染的保护性免疫机制的最佳实验模型之一。本计划项目申请的总体目标是进行全面的、多学科的努力，以确定由减毒SIV活毒株介导的免疫保护机制。由三位具有不同专业领域的主要研究人员进行的补充实验将研究：1。减毒SIV诱导的粘膜保护机制。这些实验将进行一个详细的检查的适应性和先天性免疫反应的演变引起的SIV？nef和相关的这些反应与保护，研究长期的B细胞耗竭对保护性免疫的影响，并研究病毒复制和免疫反应在女性生殖道的SIV？阴道攻击后未接种疫苗的动物。2.抗包膜免疫应答对减毒SIV介导的保护作用的贡献。具体问题包括：攻击病毒中包膜序列的错配是否会降低保护程度？用在辅助受体使用方面有显著差异的密切匹配的SIV毒株进行攻击是否会影响保护程度？使用改良单周期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.由单循环SIV（scSIV）诱导的粘液免疫和异源保护。这些实验将检查用scSIV免疫的位点是否决定T细胞应答的粘膜归巢性质和对用SIVmac 239的直肠内攻击的抗性;引发的位点是否影响病毒特异性T细胞应答保护免受用SIVmac 239的阴道攻击的能力;以及用scSIV的抗原性不同菌株的混合物免疫是否可以扩大病毒特异性免疫应答并增强对SIVmac 239的异源攻击的保护。这些研究的结果应该阐明能够保护免受HIV/SIV感染的免疫应答的性质，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（约翰逊，R.保罗） 项目1描述（由申请人提供）：缺乏关于HIV/SIV感染保护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SIV毒株接种猕猴一直被证明是诱导保护免受致病性SIV攻击的最有效手段，并提供了最佳可用实验模型来定义负责保护的特定机制。本课题组以往的研究表明，SIV特异性的CD 8 + T细胞和体液免疫应答均参与了SIV诱导的保护性免疫。nef，但尚未能够评估它们的相对重要性或新的适应性（例如CD 4 + T效应细胞）或先天性免疫应答对保护的潜在贡献。当前应用的目标是利用一些新的技术进行全面分析的作用，适应性和先天性免疫应答介导的保护诱导SIV？nef对阴道挑战，艾滋病毒传播的最重要的方式之一。具体目标包括：1：研究SIV诱导的适应性免疫和先天性免疫反应的进化过程。nef并将这些反应与针对同源和异源挑战的保护相关联。2.研究B细胞耗竭时间延长对SIV诱导的保护性免疫的影响。nef。3.研究SIV在雌性生殖道中的病毒复制、先天性和适应性免疫反应。阴道攻击后未接种疫苗的动物。

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.