Viral load and clinical disease enhancement associated with a lentivirus cytotoxic T lymphocyte vaccine regimen.
Viral load and clinical disease enhancement associated with a lentivirus cytotoxic T lymphocyte vaccine regimen.
复制标题
与慢病毒细胞毒性 T 淋巴细胞疫苗方案相关的病毒载量和临床疾病增强。
DOI：
10.1016/j.vaccine.2009.02.048
复制
发表时间：
2009
期刊：
影响因子：
5.5
通讯作者：
McGuire,TravisC
中科院分区：
文献类型：
--
作者：
Mealey,RobertH;Leib,StevenR;Littke,MattH;Wagner,Bettina;Horohov,DavidW;McGuire,TravisC
针对慢病毒的有效的基于DNA的疫苗将可能诱导针对保守病毒蛋白的CTL。马传染性贫血病毒（EIAV）感染世界各地的马，并作为一个有用的模型，慢病毒免疫控制。尽管减毒活疫苗能诱导保护性免疫应答，但DNA疫苗不能。特别是，基于DNA的疫苗在诱导针对马细胞内病原体的CTL应答方面取得了有限的成功。我们假设，用编码EIAV Gag p15/p26的密码子优化的质粒与编码马IL-2/IgG融合蛋白的质粒作为分子佐剂共同给药，然后用表达Gag p15/p26的牛痘载体加强免疫，将诱导保护性Gag特异性CTL应答。尽管该方案在7匹接种马中的4匹中诱导了GAG特异性CTL，但直到牛痘加强后才检测到CTL，并且在EIAV攻击的疫苗中未观察到保护作用。出乎意料的是，疫苗接种者具有显著更高的病毒载量和更严重的临床疾病，与疫苗诱导的CTL的存在相关。结论是（1）需要进一步优化DNA免疫的时间和途径以在体内有效地引发CTL，（2）IL-2/IgG质粒的共施用不增强Gag p15/p26质粒的CTL引发，（3）牛痘载体可用于在马中诱导慢病毒特异性CTL，（4）单独的GAG特异性CTL是不够的，或者需要更强的GAG特异性CTL应答来限制EIAV病毒血症和临床疾病，和（5）缺乏包膜免疫原的CTL诱导疫苗可导致慢病毒疾病增强。尽管与此疫苗方案相关的增强机制仍有待阐明，但这些结果对慢病毒T细胞疫苗的开发具有重要意义。
Effective DNA-based vaccines against lentiviruses will likely induce CTL against conserved viral proteins. Equine infectious anemia virus (EIAV) infects horses worldwide, and serves as a useful model for lentiviral immune control. Although attenuated live EIAV vaccines have induced protective immune responses, DNA-based vaccines have not. In particular, DNA-based vaccines have had limited success in inducing CTL responses against intracellular pathogens in the horse. We hypothesized that priming with a codon-optimized plasmid encoding EIAV Gag p15/p26 with co-administration of a plasmid encoding an equine IL-2/IgG fusion protein as a molecular adjuvant, followed by boosting with a vaccinia vector expressing Gag p15/p26, would induce protective Gag-specific CTL responses. Although the regimen induced Gag-specific CTL in four of seven vaccinated horses, CTL were not detected until after the vaccinia boost, and protective effects were not observed in EIAV challenged vaccinates. Unexpectedly, vaccinates had significantly higher viral loads and more severe clinical disease, associated with the presence of vaccine-induced CTL. It was concluded that (1) further optimization of the timing and route of DNA immunization was needed for efficient CTL priming in vivo, (2) co-administration of the IL-2/IgG plasmid did not enhance CTL priming by the Gag p15/p26 plasmid, (3) vaccinia vectors are useful for lentivirus-specific CTL induction in the horse, (4) Gag-specific CTL alone are either insufficient or a more robust Gag-specific CTL response is needed to limit EIAV viremia and clinical disease, and (5) CTL-inducing vaccines lacking envelope immunogens can result in lentiviral disease enhancement. Although the mechanisms for enhancement associated with this vaccine regimen remain to be elucidated, these results have important implications for development of lentivirus T cell vaccines.