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Oncolytic Engineering of icp34.5 and LAT of Herpes Simplex Virus Type 1

Yangtze Medicine 2021年第2期5卷 106-116页

作者： Wenqi Cai Ying Zhang Qi Huang Ying Xiang Hongwu Xin Laboratory of Oncology Center for Molecular Medicine School of Basic Medicine Health Science Center Yangtze University Jingzhou China Department of Biochemistry and Molecular Biology School of Basic Medicine Health Science Center Yangtze University Jingzhou China

Oncolytic virus (OV) is a kind of virus that can preferentially infect and kill tumor cells. The second oncolytic virus drug was oncolytic herpes simplex virus (oHSV) Talimogene Laherparepvec (T-VEC). HSV-1 infectious cell culture protein 34.5 (icp34.5) and latency-associated transcript (LAT) genes are closely related to virus selective infection and latent infection. Their engineering is essential for constructing efficient and safe oHSV. We summarized the mechanisms of icp34.5 and LAT in the course of HSV-1 infection and reviewed the engineered oHSVs. We are aimed to provide an insight in developing oHSV in the future.

关键词： Herpes Simplex Virus Oncolytic Herpes Simplex Virus Latency-Associated Transcript icp34.5

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单纯疱疹病毒蛋白icp34.5的抗凋亡功能探索

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南开大学学报（自然科学版） 2014年第6期47卷 40-44页

作者：杨寅王雨杨鑫徐昱徐冰张翠竹南开大学生命科学学院天津300071

单纯疱疹病毒(HSV)是一种高感染率的人类DNA病毒,HSV进化出多种机制拮抗人体免疫系统的抗病毒免疫,其中抗凋亡是HSV的重要机制之一.有多种HSV病毒蛋白具有抗凋亡功能.该论文通过多种凋亡表型证明icp34.5也具有抗凋亡功能.进一步实验确定... 详细信息

单纯疱疹病毒(HSV)是一种高感染率的人类DNA病毒,HSV进化出多种机制拮抗人体免疫系统的抗病毒免疫,其中抗凋亡是HSV的重要机制之一.有多种HSV病毒蛋白具有抗凋亡功能.该论文通过多种凋亡表型证明icp34.5也具有抗凋亡功能.进一步实验确定icp34.5是抑制了线粒体及其上游的凋亡通路.icp34.5通过拮抗宿主细胞凋亡促进了病毒自身的复制.

关键词： HSV icp34.5 细胞凋亡

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Persistent inflammation and neuronal loss in the mouse brain induced by a modified form of attenuated herpes simplex virus type I

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Virologica Sinica 2023年第1期38卷 108-118页

作者： Erlin Wang Xinwei Huang Yunshuang Ye Shiqing Zou Guijun Chen Liping Yang Nigel W.Fraser Fukai Bao Jumin Zhou Xia Cao Key Laboratory of Second Affiliated Hospital of Kunming Medical University Kunming650000China Key Laboratory of Animal Models and Human Disease Mechanism of the Chinese Academy of Science/Key Laboratory of Healthy Aging Research of Yunnan Province Kunming Institute of ZoologyThe Chinese Academy of SciencesKunming650223China Kunming College of Life Science University of Chinese Academy of SciencesKunming650204China Department of Microbiology Perelman School of MedicineUniversity of PennsylvaniaPhiladelphiaPA19104USA Department of Biology and Immunology Kunming Medical UniversityKunming650101China KIZ/CUHK Joint Laboratory of Bioresources and Molecular Research in Common Diseases Kunming650223China

Herpes simplex virus-1(HSV-1)is a widespread neurotropic virus that can reach the brain and cause a rare but acute herpes simplex encephalitis(HSE)with a high mortality rate.Most patients present with changes in neurological and behavioral status,and survivors suffer long-term neurological sequelae.To date,the pathogenesis leading to brain damage is still not well understood.HSV-1 induced encephalitis in the central nervous system(CNS)in animals are usually very diffuse and progressing rapidly,and mostly fatal,making the analysis difficult.Here,we established a mouse model of HSE via intracerebral inoculation of modified version of neuralattenuated strains of HSV-1(deletion of icp34.5 and inserting a strong promoter into the latency-associated transcript region),in which the LMR-αΔpA strain initiated moderate productive infection,leading to strong host immune and inflammatory response characterized by persistent microglia activation.This viral replication activity and prolonged inflammatory response activated signaling pathways in neuronal damage,amyloidosis,Alzheimer's disease,and neurodegeneration,eventually leading to neuronal loss and behavioral changes characterized by hypokinesia.Our study reveals detailed pathogenic processes and persistent inflammatory responses in the CNS and provides a controlled,mild and non-lethal HSE model for studying long-term neuronal injury and increased risk of neurodegenerative diseases due to HSV-1 infection.

关键词： Herpes simplex virus-1(HSV-1) Herpes simplex encephalitis(HSE) icp34.5 Neuroinflammation Neuronal loss

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Ei sh单纯疱疹病毒1型icp34.5在Vero细胞的表达及对Bax/Bcl-2的影响

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现代预防医学 2015年第21期42卷 3969-3972页

作者：闪海霞范崇桂张怀宏霍丽亚翟玉峰河南省南阳市中心医院感染性疾病科

目的构建单纯疱疹病毒1型(HSV-1)真核表达载体pm R-mcherry-icp34.5,验证icp34.5对宿主细胞Bax、Bcl-2 m RNA相对表达量及对Bax/Bcl-2的影响。方法以提取HSV-1病毒DNA为模版,PCR扩增HSV-1 icp34.5序列,双酶切连接至pm R-mcherry真核表达载体上,并对重组真核表达载体进行验证,然后重组载体瞬时转染Vero细胞,m RNA水平表达用逆转录PCR方法检测,融合蛋白的表达的检测用荧光显微镜,MTT检测对Vero的细胞活性,喜树碱诱导凋亡后,实时定量PCR检测Bax、Bcl-2 m RNA在细胞中的相对表达量。结果转染后RT-PCR验证有目的基因的转录,荧光显微镜观察到融合蛋白在转染的Vero细胞中表达。重组质粒可以抵消空质粒对细胞的损伤作用,转染重组质粒的Vero细胞和正常细胞的中Bax m RNA表达量和Bcl-2 m RNA表达量相差不大,但Bax/Bcl-2得比值明显低于转染pm R-mcherry空质粒的Vero细胞和正常加药的Vero细胞。结论 pm R-mcherry-icp34.5真核表达载体能在Vero细胞中高效表达,并能减弱空质粒转染对细胞活性作用,icp34.5能使Vero细胞中Bax/Bcl-2稳定性增强,使细胞抗凋亡。

关键词：单纯疱疹病毒1型 icp34.5 Vero Bax Bcl-2

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Gene Therapy for Cancer by Mutant HSV Deleted Apoptosis-Inhibited Gene

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Wuhan University Journal of Natural Sciences 2000年第3期5卷 377-378页

作者： Lan, Ping Qi, Yi-peng Xiao, Geng-fu Institute of Virology Wuhan UniversityWuhan430072

A mutant HSV(mtHSV) deleted icp34.5,an apoptosis-inhibiting gene w a s constructed. It is supposed that the mtHSV can replicate in p53-deficient cel l s selectively and lead to oncolysis targetedly. Mice tumor model harboring sarco ma cell line s-180 was developed and the mtHSV was injected into the tumors. We found that the mean volume and weight of tumors of early therapeutic group(ETG) were reduced 49.29% and 38.31% of that of control tumors .In t he mid\|term group(MTG),the redutcion rate were 26.9% and 24.52% respectively.

关键词： cancer HSV icp34.5 gene therapy

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Tumor-targeted Therapy with Replication-conditional Mutant of HSV-1 Induces Regression of Xenografted Human Hepatomas

Tumor-targeted Therapy with Replication-conditional Mutant o...

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2006年度学术研讨会

作者： Feng Xue Chang-yuan Dong Yue Su Hua-bing Zhu Bao-li Hu Yi-pengQi Key Laboratory of Virology, Ministry of Education, College of Life Sciences, Wuhan University, 430072, Wuhan, Hubei Province, P. R. China.Medicine School, Whuhan University, 430072, Whuhan, Hubei Province, P. R. China.

The selectively oncolytic effects of mtHSV, a HSV icp34.5 mutant with lacz gene insertion, on several tumor cells in vitro and its antitumor effects by the intratumoral (IT) route to nude mice body loaded the human hepatoma xenografts were explored. The mtHSV could conditionally replicate in and lysed Hep-3B (human hepatoma cells), Hep-2 (human larynx cancer cells) and SPC-A1 (human lung cancer cells), but not MRC-5 (human fibroblast cells). The 125 nude mice with Hep-3B were randomized into five treatment groups and given three IT injections of three dose of the mtHSV, adriamycin (ADM), or vehicle (supernatant of non-infected Vero cells). Significant tumor growth inhibition (30%--70%) was seen in the nude mice treated IT with mtHSV, whereas tumors treated IT with Vero supernatant displayed rapid tumor growth. The results of regular and biochemical blood examination, systemic necropsy, and pathological slices showed that mtHSV almost has no side effect on treated mice. RT-PCR results revealed that mtHSV replication was exclusively confined to the treated tumors, but not other organs. Our results provide a further preclinical evidence that mtHSV may be used as an oncolytic agent for cancer therapy.

关键词： herpes simplex virus type 1 icp34.5 hepatoma xenografts cancer therapy

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