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: 7786184
• 负责人: R. PAUL JOHNSON
• 金额: $ 337.06万
• 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/7786184
• 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.

描述（由申请人提供）：缺乏有关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。事实证明，用 SIV 减毒株对猕猴进行疫苗接种是诱导猕猴免受致病性 SIV 攻击的最有效方法。因此，对接种减毒 SIV 毒株的猕猴进行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。该计划项目申请的总体目标是进行全面的、多学科的努力，以确定由减毒活 SIV 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检查： 1. 减毒 SIV 诱导的粘膜保护机制。这些实验将详细检查 SIV?nef 诱导的适应性和先天免疫反应的演变，并将这些反应与保护联系起来，检查长期 B 细胞耗竭对保护性免疫的影响，并研究阴道攻击后 SIV?nef 疫苗接种动物的雌性生殖道中的病毒复制和免疫反应。 2.抗包膜免疫反应对减毒活SIV介导的保护的贡献。具体问题包括：攻击病毒中包膜序列的不匹配是否会降低保护程度？使用辅助受体使用情况显着不同的密切匹配的 SIV 毒株进行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（scSIV）诱导的粘膜免疫和异源保护。这些实验将检查 scSIV 免疫位点是否决定 T 细胞反应的粘膜归巢特性以及对 SIVmac239 直肠内攻击的抵抗力；引发位点是否会影响病毒特异性 T 细胞反应抵御 SIVmac239 阴道攻击的能力；以及使用具有不同抗原性的 scSIV 菌株的混合物进行免疫是否可以扩大病毒特异性免疫反应并增强对 SIVmac239 异源攻击的保护。这些研究的结果应该揭示能够预防 HIV/SIV 感染的免疫反应的本质，这仍然是艾滋病疫苗研究中悬而未决的突出问题之一，因此将对临床适用的艾滋病疫苗的设计产生重要影响。 项目 1：减毒 SIV 诱导的粘膜保护机制 (Johnson, R. Paul) 项目 1 描述（由申请人提供）：缺乏有关 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。猕猴接种 SIV 减毒株已被一致证明是针对致病性 SIV 攻击诱导保护的最有效方法，并提供了最佳的实验模型来定义负责保护的具体机制。我们小组之前的研究提供了证据，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，但无法评估它们的相对重要性或新型适应性（例如 CD4+ T 效应细胞）或先天免疫反应对保护的潜在贡献。当前应用的目标是利用多种新技术对适应性和先天免疫反应在介导 SIV?nef 诱导的针对阴道攻击（HIV 传播最重要的模式之一）的保护中的作用进行全面分析。具体目标包括： 1：检查 SIV?nef 诱导的适应性和先天免疫反应的演变，并将这些反应与针对同源和异源攻击的保护联系起来。图 2：检查长期 B 细胞耗竭对 SIV?nef 诱导的保护性免疫的影响。图 3：检查 SIV-nef 疫苗接种动物阴道攻击后雌性生殖道中的病毒复制、先天性和适应性免疫反应。