Mechanisms of protective immunity induced by live attenuated SIV vaccines

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毒株接种猕猴一直被证明是最有效的诱导 保护猕猴免受病原性SIV攻击。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调查人员进行的补充实验将检验： 1.减毒SIV诱导的粘膜保护机制这些实验将对SIVAnef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，检查B细胞长期耗尽对保护性免疫的影响，以及研究SIVAnef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？使用改良的单周期SIV诱导的抗包膜抗体反应强度的变化是否会影响保护程度？ 3.单周期SIV(Single-Cycle SIV，ScSIV)诱导的粘膜免疫与异种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。

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 SIVAnef 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 SIVAnefvaccinated 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.