Chimeric papillomavirus virus-like particles elicit antitumor immunity against the E7 oncoprotein in an HPV16 tumor model
Chimeric papillomavirus virus-like particles elicit antitumor immunity against the E7 oncoprotein in an HPV16 tumor model
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DOI：
10.1073/pnas.95.4.1800
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发表时间：
1998-02-17
影响因子：
11.1
通讯作者：
Schiller, JT
中科院分区：
文献类型：
--
作者：
Greenstone, HL;Nieland, JD;Schiller, JT
乳头瘤病毒样颗粒（VLP）是预防人乳头瘤病毒（HPV）感染及其相关上皮瘤变的一种有希望的疫苗候选物，但由于在感染上皮细胞的增殖细胞或宫颈癌中未检测到病毒颗粒衣壳蛋白，因此它们不太可能具有治疗效果。我们已经产生了稳定的嵌合VLP，其由L1主要衣壳蛋白加上与L2次要衣壳蛋白融合的整个E7（11 kDa）或E2（43 kDa）非结构性乳头瘤病毒蛋白组成。嵌合VLP在其形态学和其凝集红细胞并引发高滴度中和抗体的能力方面与亲本VLP不可区分。通过使用表达HPV 16 E7但不表达病毒体结构蛋白的肿瘤细胞系TC-1在C57 BL/6小鼠中测试对肿瘤攻击的保护。而不是HPV 16 L1/L2 VLP，保护小鼠免受肿瘤攻击，即使在没有佐剂的情况下。嵌合VLP还在主要组织相容性II类缺陷小鼠中诱导针对肿瘤攻击的保护，但在β（2）-微球蛋白或穿孔素敲除小鼠中不诱导，这意味着保护是由I类限制性细胞毒性淋巴细胞介导的。含有乳头瘤病毒非结构蛋白的嵌合VLP可增加基于VLP的预防性疫苗在人类中的治疗潜力。
Papillomavirus-like particles (VLPs) are a promising prophylactic vaccine candidate to prevent human papillomavirus (HPV) infections and associated epithelial neoplasia, However, they are unlikely to have therapeutic effects because the virion capsid proteins are not detected in the proliferating cells of the infected epithelia or in cervical carcinomas, To increase the number of viral antigen targets for cell-mediated immune responses in VLP-based vaccine,,ve have generated stable chimeric VLPs consisting of the L1 major capsid protein plus the entire E7 (11 kDa) or E2 (43 kDa) nonstructural papillomavirus protein fused to the L2 minor capsid protein. The chimeric VLPs are indistinguishable from the parental VLPs in their morphology and in their ability to agglutinate erythrocytes and elicit high titers of neutralizing antibodies, Protection from tumor challenge was tested in C57BL/6 mice by using the tumor cell line TC-1, which expresses HPV16 E7, but not the virion structural proteins, Injection of HPV16 L1/L2-HPV16 E7 chimeric VLPs, but not HPV16 L1/L2 VLPs, protected the mice from tumor challenge, even in the absence of adjuvant. The chimeric VLPs also induced protection against tumor challenge in major histocompatibility class II-deficient mice, but not in beta(2)-microglobulin or perforin knockout mice implying that protection was mediated by class I-restricted cytotoxic lymphocytes, These findings raise the possibility that VLPs may generally be efficient vehicles for generating cell-mediated immune responses and that, specifically, chimeric VLPs containing papillomavirus nonstructural proteins may increase the therapeutic potential of VLP-based prophylactic vaccines in humans.