Protective CMI mechanisms of a dual-subtype FIV vaccine

项目摘要/摘要 原型和商用双亚型FIV疫苗，由灭活的A和D亚型组成 菌株，对同源亚型、A/B重组亚型和 异源亚型B挑战。双亚型FIV疫苗对猫的免疫保护机制 应该为人类有效的HIV-1/AIDS疫苗的开发提供洞察力。被动性 纯化双亚型FIV疫苗免疫雏猫的免疫效果 为受体猫提供保护，使其免受同源亚型的影响，这与 存在疫苗诱导的病毒中和抗体(VNA)。相比之下，被动保护是 不能用VNA抗性菌株对抗异源B亚型挑战。此外，领养 从免疫猫到MHC配型猫的T细胞富集群的转移(A-T)保护了 A-T受体对抗同源和异源挑战。双亚型疫苗接种 提供了联合免疫途径(皮下、皮内、经皮和鼻腔) 针对同源阴道挑战的保护。这些结果来自上一个供资周期 提示对疫苗诱导的VNA敏感株(同源亚型)的保护作用 毒株)由VNA免疫和细胞免疫(CMI)介导，而疫苗具有保护作用 抗异源亚型菌株是由CMI介导的。关于竞争更新的研究 GRANT的目的是识别T细胞的表型和功能以及病毒表位 以及负责双亚型疫苗保护的MHC概况(具体目标1)。建议数 研究还将确定最佳接种途径(S)和疫苗保护机制 用来自同源或异源的异源菌株对抗粘膜-阴道攻击 亚型(特定目标2)。这些研究的最终目标是提供关于哪些病毒 成分、宿主免疫反应、MHC特征和疫苗接种途径对 有效预防艾滋病毒-1的主要传播方式(粘膜和静脉传播) 在人类身上。项目叙事 自那以来，已售出超过180万剂商用猫免疫缺陷病毒(FIV)疫苗 2002年7月，没有任何疫苗失败病例。FIV导致宠物猫患上猫咪艾滋病，并在全球范围内 流行率与HIV-1相似。流行性出血热疫苗的保护机制和病毒蛋白 对这种保护的重要性将在这项赠款的拟议研究中确定。调查结果来自 这些研究应该会促进我们对如何设计有效的HIV-1疫苗的理解 人类。

PROJECT SUMMARY / ABSTRACT Prototype and commercial dual-subtype FIV vaccines, consisting of inactivated subtype-A and -D strains, conferred sterilizing protection against homologous subtype, subtype-A/B recombinant, and heterologous subtype-B challenges. The mechanisms of dual-subtype FIV vaccine protection in cats should provide insights to the development of effective HIV-1/AIDS vaccine in humans. Passive antibody immunization with purified dual-subtype FIV vaccine-induced immunoglobulin to na¿ve cats afforded protection of the recipient cats against homologous subtype, which correlated with the presence of vaccine-induced virus neutralizing antibodies (VNA). In contrast, passive protection was not achieved against heterologous subtype-B challenge with VNA-resistant strain. Moreover, adoptive transfer (A-T) of T-cell enriched population from vaccinated cats to MHC-matched cats protected the A-T recipient against homologous and heterologous challenges. Dual-subtype vaccination using combined immunization routes (subcutaneous, intradermal, transcutaneous, & intranasal) afforded protection against homologous vaginal challenge. These results from the previous funding cycle suggest that protection against vaccine-induced VNA-susceptible strains (homologous subtype strains) is mediated by both VNA immunity and cell-mediated immunity (CMI), while vaccine protection against heterologous subtype strains is mediated by CMI. The studies in the competitive renewal grant are aimed at identifying the phenotypes and functions of the T cells as well as the viral epitopes and MHC profiles responsible for the dual-subtype vaccine protection (Specific aim 1). The proposed studies will also identify the best vaccination route(s) and the mechanisms of vaccine protection against mucosal-vaginal challenges with heterologous strains from homologous or heterologous subtype (Specific aim 2). The ultimate goal of these studies is to provide insights about which viral components, host immune responses, MHC profiles, and vaccination routes are important for an effective prophylaxis against the predominant transmission modes (mucosal and intravenous) of HIV-1 in humans. PROJECT NARRATIVE Over 1.8 million doses of commercial feline immunodeficiency virus (FIV) vaccine have been sold since July 2002 without any cases of vaccine failure. FIV causes feline AIDS in pet cats and has worldwide prevalence similar to HIV-1. The mechanisms of this FIV vaccine protection and viral proteins important for such protection will be determined in the proposed studies of this grant. Findings from these studies should advance our understanding about how to design an effective HIV-1 vaccine in humans.