Protective immunity against ocular herpes infection and disease induced by highly immunogenic self-adjuvanting glycoprotein D lipopeptide vaccines
Protective immunity against ocular herpes infection and disease induced by highly immunogenic self-adjuvanting glycoprotein D lipopeptide vaccines
复制标题
DOI：
10.1167/iovs.07-0356
复制
发表时间：
2007-10-01
影响因子：
4.4
通讯作者：
BenMohamed, Lbachir
中科院分区：
文献类型：
--
作者：
Bettahi, Ilham;Nesburn, Anthony B.;BenMohamed, Lbachir
目的。眼单纯疱疹病毒1型（HSV-1）亚单位疫苗开发的一个重要阶段是鉴定一种有效、安全、无佐剂的抗原递送系统，该系统能够诱导和维持长期记忆t细胞保护性免疫。本研究旨在验证在眼部疱疹小鼠模型中，携带HSV-1糖蛋白D (gD) T细胞表位的自佐剂脂肽免疫可引发长期hsv特异性T细胞并减少感染、疾病或两者兼有的假设。最近从HSV-1 gD中鉴定出5个免疫优势的CD4(+) t细胞肽表位（gD（1-29）、gD（49-82）、gD（146-179）、gD（228-257）和gD(332-358)），它们与棕榈酸片段（脂肽）共价连接，并在无佐剂的生理盐水中皮下传递。这些分子定义的脂肽诱导的原代T细胞和记忆T细胞及其保护功效，从病毒在眼睛中的复制、眼部疾病和存活的角度进行了评估。在体外驱动树突状细胞成熟的三种gD脂肽，诱导了长期的、病毒特异性的、产生ifn - γ的CD4(+) Th-1反应，与眼部疱疹感染和疾病的减少有关。用这三种高免疫原性Th-1脂肽混合免疫可提高存活率，降低眼部病毒滴度峰值，清除眼部疾病。接种含有新型HSV-1免疫优势gD t细胞表位的混合自佐剂脂肽可保护小鼠免受眼部疱疹感染和疾病。这些脂肽诱导的保护性免疫的强度及其安全性提供了一种分子定义的疫苗制剂，可以对抗人类眼部疱疹感染和疾病。
PURPOSE. An important phase in the development of an ocular herpes simplex virus type 1 (HSV-1) subunit vaccine is the identification of an efficient, safe, and adjuvant-free antigen delivery system capable of inducing and sustaining long-term memory T-cell protective immunity. This study was conducted to test the hypothesis that immunization with self-adjuvanting lipopeptide bearing HSV-1 glycoprotein D (gD) T-cell epitopes would elicit long-term HSV-specific T cells and decrease infection, disease, or both in a ocular herpes mouse model.METHODS. Five immunodominant CD4(+) T-cell peptide epitopes ( gD(1-29), gD(49-82), gD(146-179), gD(228-257), and gD(332-358)), recently identified from HSV-1 gD, were covalently linked to a palmitic acid moiety (lipopeptides) and delivered subcutaneously in adjuvant-free saline. The primary and memory T cells induced by these molecularly defined lipopeptides and their protective efficacy were assessed, in terms of virus replication in the eye, ocular disease, and survival.RESULTS. Three gD lipopeptides, that drive dendritic cell maturation in vitro, induced long-term, virus-specific, IFN-gamma-producing CD4(+) Th-1 responses, associated with a reduction in ocular herpes infection and disease. Immunization with a cocktail of these three highly immunogenic Th-1 lipopeptides increased survival, lowered the peak of ocular virus titer, and cleared the ocular disease.CONCLUSIONS. Vaccination with a mixture self-adjuvanting lipopeptides containing novel HSV-1 immunodominant gD T-cell epitopes protected mice from ocular herpes infection and disease. The strength of protective immunity induced by these lipopeptides together with their safety provide a molecularly defined vaccine formulation that could combat ocular herpes infection and disease in humans.