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首页> 外文期刊>Human gene therapy >Long-term protection against human papillomavirus e7-positive tumor by a single vaccination of adeno-associated virus vectors encoding a fusion protein of inactivated e7 of human papillomavirus 16/18 and heat shock protein 70.
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Long-term protection against human papillomavirus e7-positive tumor by a single vaccination of adeno-associated virus vectors encoding a fusion protein of inactivated e7 of human papillomavirus 16/18 and heat shock protein 70.

机译：通过单次接种编码人乳头瘤病毒16/18灭活e7融合蛋白和热休克蛋白70的腺相关病毒载体，长期预防人乳头瘤病毒e7阳性肿瘤。

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摘要

We investigated a gene vaccine strategy against human papillomavirus (HPV)-induced cancer and premalignant diseases, using adeno-associated virus (AAV) vector encoding the viral E7 oncoproteins as the tumor antigens from HPV serotypes 16 (HPV16) and 18 (HPV18). Genetically inactivated E7 proteins were fused with a heat shock protein 70 (hsp70) to minimize the risk of cell transformation and enhance immune responses. The fusion protein gene was packaged in AAV serotype 1 or 2 (AAV1 or 2) for efficient in vivo gene expression. Our results showed that after a single intramuscular injection, the AAV1 vector elicited stronger HPV-specific cytotoxic T lymphocyte (CTL) responses and interferon-gamma secretion when compared with the AAV2 vector. Prophylactic immunization with AAV1 protected 100% of the mice from tumor growth for more than 1 year, whereas all the control mice immunized with either a LacZ vector or saline grew large tumors and died within 6 weeks after inoculation of E7-positive tumor cell line TC-1. In addition, this single-dose AAV1 vaccination completely protected the mice against second and third challenges with higher numbers of TC-1 cells. Despite lower CTL responses against the E7 antigens, AAV2 vector prophylactic immunization was also sufficient to protect 100% of the mice against the initial and second tumor challenges and 70% of the mice against the third challenge. In addition, therapeutic immunization with AAV1 after palpable tumor formation inhibited tumor growth and caused tumor regression in some mice. Thus, our studies support the potential of AAV vectors as a genetic vaccine for the prevention and treatment of HPV-induced malignancies.
机译：我们使用编码病毒E7癌蛋白的腺相关病毒（AAV）载体作为HPV血清型16（HPV16）和18（HPV18）的肿瘤抗原，研究了针对人乳头瘤病毒（HPV）诱导的癌症和癌前疾病的基因疫苗策略。将基因灭活的E7蛋白与热激蛋白70（hsp70）融合在一起，以最大程度地降低细胞转化的风险并增强免疫反应。将融合蛋白基因包装在AAV血清型1或2（AAV1或2）中，以进行有效的体内基因表达。我们的结果表明，与AAV2载体相比，单次肌内注射后，AAV1载体引起更强的HPV特异性细胞毒性T淋巴细胞（CTL）反应和干扰素-γ分泌。用AAV1进行的预防性免疫可保护100％的小鼠免受肿瘤生长超过1年的影响，而所有用LacZ载体或生理盐水免疫的对照小鼠均会生长大肿瘤，并在接种E7阳性肿瘤细胞系TC后6周内死亡-1。此外，这种单剂量AAV1疫苗完全保护了小鼠免受TC-1细胞数量增加的第二次和第三次攻击。尽管针对E7抗原的CTL反应较低，但AAV2载体预防性免疫也足以保护100％的小鼠免受初始和第二次肿瘤攻击，而70％的小鼠免受第三次攻击。此外，可触知的肿瘤形成后用AAV1进行的治疗性免疫抑制了某些小鼠的肿瘤生长并导致肿瘤消退。因此，我们的研究支持AAV载体作为预防和治疗HPV诱发的恶性肿瘤的基因疫苗的潜力。

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