Protective CMI mechanisms of a dual-subtype FIV vaccine

描述（由申请人提供）：原型和商业双亚型FIV疫苗，由灭活亚型a和d菌株组成，具有对同源亚型、亚型a /B重组和异源亚型B挑战的杀菌保护作用。猫双亚型FIV疫苗保护的机制应该为开发有效的人类HIV-1/AIDS疫苗提供见解。用纯化的双亚型FIV疫苗诱导的免疫球蛋白对初生猫进行被动抗体免疫，可以保护受体猫免受同源亚型FIV的侵害，这与疫苗诱导的病毒中和抗体（VNA）的存在有关。相比之下，vna抗性菌株对异源b亚型攻毒没有实现被动保护。此外，将接种过疫苗的猫的t细胞富集群体过继转移（A-T）到mhc匹配的猫，可以保护A-T受体免受同源和异源攻击。采用联合免疫途径（皮下、皮内、经皮和鼻内）的双亚型疫苗接种提供了对同源阴道攻击的保护。来自上一个资助周期的这些结果表明，对疫苗诱导的VNA易感菌株（同源亚型菌株）的保护是由VNA免疫和细胞介导免疫（CMI）介导的，而疫苗对异源亚型菌株的保护是由CMI介导的。竞争性更新资助的研究旨在确定T细胞的表型和功能，以及负责双亚型疫苗保护的病毒表位和MHC谱（特异性目标1）。拟议的研究还将确定最佳的疫苗接种途径和疫苗保护机制，以抵御来自同源或异源亚型的异源菌株对粘膜阴道的攻击（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谱和疫苗接种途径对于有效预防人类HIV-1的主要传播模式（粘膜和静脉）是重要的。公共卫生相关性：自2002年7月以来，已销售了180多万剂商业猫免疫缺陷病毒（FIV）疫苗，没有任何疫苗失败的病例。FIV在宠物猫中引起猫艾滋病，与HIV-1相似，在世界范围内流行。这种FIV疫苗的保护机制和对这种保护至关重要的病毒蛋白将在这项拨款的拟议研究中确定。这些研究的发现应该促进我们对如何设计一种有效的人类HIV-1疫苗的理解。

DESCRIPTION (provided by applicant): 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 naive 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. PUBLIC HEALTH RELEVANCE: 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.