Oncolytic herpes simplex virus armed with a bacterial GBP1 degrader improves antitumor activity
Oncolytic viruses (OVs) encoding various transgenes are being evaluated for cancer immunotherapy. Diverse factors such as cytokines, immune checkpoint inhibitors, tumor-associated antigens, and T cell engagers have been exploited as transgenes. These modifications are primarily aimed to reverse the...
| Main Authors: | , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2023-06-01
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| Series: | Molecular Therapy: Oncolytics |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2372770523000311 |
| _version_ | 1797828117610364928 |
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| author | Jun Xie Shaowei Wang Yunhong Zhong Ming Gao Xuezhang Tian Liting Zhang Dongli Pan Qingsong Qin Bing Wu Ke Lan Zhi-Jun Sun Junjie Zhang |
| author_facet | Jun Xie Shaowei Wang Yunhong Zhong Ming Gao Xuezhang Tian Liting Zhang Dongli Pan Qingsong Qin Bing Wu Ke Lan Zhi-Jun Sun Junjie Zhang |
| author_sort | Jun Xie |
| collection | DOAJ |
| description | Oncolytic viruses (OVs) encoding various transgenes are being evaluated for cancer immunotherapy. Diverse factors such as cytokines, immune checkpoint inhibitors, tumor-associated antigens, and T cell engagers have been exploited as transgenes. These modifications are primarily aimed to reverse the immunosuppressive tumor microenvironment. By contrast, antiviral restriction factors that inhibit the replication of OVs and result in suboptimal oncolytic activity have received far less attention. Here, we report that guanylate-binding protein 1 (GBP1) is potently induced during HSV-1 infection and restricts HSV-1 replication. Mechanistically, GBP1 remodels cytoskeletal organization to impede nuclear entry of HSV-1 genome. Previous studies have established that IpaH9.8, a bacterial E3 ubiquitin ligase, targets GBPs for proteasomal degradation. We therefore engineered an oncolytic HSV-1 to express IpaH9.8 and found that the modified OV effectively antagonized GBP1, replicated to a higher titer in vitro and showed superior antitumor activity in vivo. Our study features a strategy for improving the replication of OVs via targeting a restriction factor and achieving promising therapeutic efficacy. |
| first_indexed | 2024-04-09T12:59:44Z |
| format | Article |
| id | doaj.art-623e5979b18a480f934fa23257207744 |
| institution | Directory Open Access Journal |
| issn | 2372-7705 |
| language | English |
| last_indexed | 2024-04-09T12:59:44Z |
| publishDate | 2023-06-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Molecular Therapy: Oncolytics |
| spelling | doaj.art-623e5979b18a480f934fa232572077442023-05-13T04:25:18ZengElsevierMolecular Therapy: Oncolytics2372-77052023-06-01296176Oncolytic herpes simplex virus armed with a bacterial GBP1 degrader improves antitumor activityJun Xie0Shaowei Wang1Yunhong Zhong2Ming Gao3Xuezhang Tian4Liting Zhang5Dongli Pan6Qingsong Qin7Bing Wu8Ke Lan9Zhi-Jun Sun10Junjie Zhang11The State Key Laboratory Breeding Base of Basic Science of Stomatology & Key Laboratory of Oral Biomedicine Ministry of Education, School & Hospital of Stomatology, State Key Laboratory of Virology, Medical Research Institute, Wuhan University, Wuhan 430071, China; Frontier Science Center for Immunology and Metabolism, Wuhan University, Wuhan 430071, ChinaThe State Key Laboratory Breeding Base of Basic Science of Stomatology & Key Laboratory of Oral Biomedicine Ministry of Education, School & Hospital of Stomatology, State Key Laboratory of Virology, Medical Research Institute, Wuhan University, Wuhan 430071, China; Frontier Science Center for Immunology and Metabolism, Wuhan University, Wuhan 430071, ChinaThe State Key Laboratory Breeding Base of Basic Science of Stomatology & Key Laboratory of Oral Biomedicine Ministry of Education, School & Hospital of Stomatology, State Key Laboratory of Virology, Medical Research Institute, Wuhan University, Wuhan 430071, China; Frontier Science Center for Immunology and Metabolism, Wuhan University, Wuhan 430071, ChinaThe State Key Laboratory Breeding Base of Basic Science of Stomatology & Key Laboratory of Oral Biomedicine Ministry of Education, School & Hospital of Stomatology, State Key Laboratory of Virology, Medical Research Institute, Wuhan University, Wuhan 430071, China; Frontier Science Center for Immunology and Metabolism, Wuhan University, Wuhan 430071, ChinaThe State Key Laboratory Breeding Base of Basic Science of Stomatology & Key Laboratory of Oral Biomedicine Ministry of Education, School & Hospital of Stomatology, State Key Laboratory of Virology, Medical Research Institute, Wuhan University, Wuhan 430071, China; Frontier Science Center for Immunology and Metabolism, Wuhan University, Wuhan 430071, ChinaThe State Key Laboratory Breeding Base of Basic Science of Stomatology & Key Laboratory of Oral Biomedicine Ministry of Education, School & Hospital of Stomatology, State Key Laboratory of Virology, Medical Research Institute, Wuhan University, Wuhan 430071, China; Frontier Science Center for Immunology and Metabolism, Wuhan University, Wuhan 430071, ChinaState Key Laboratory for Diagnosis and Treatment of Infectious Diseases, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China; Department of Medical Microbiology and Parasitology, Zhejiang University School of Medicine, Hangzhou 310058, ChinaLaboratory of Human Virology and Oncology, Shantou University Medical College, Shantou, Guangdong 515041, ChinaFrontier Science Center for Immunology and Metabolism, Wuhan University, Wuhan 430071, ChinaFrontier Science Center for Immunology and Metabolism, Wuhan University, Wuhan 430071, China; State Key Laboratory of Virology, School of Life Sciences, Wuhan University, Wuhan 430072, ChinaThe State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei-MOST) & Key Laboratory of Oral Biomedicine Ministry of Education, School & Hospital of Stomatology, Wuhan University, Wuhan 430079, China; Corresponding author: Zhi-Jun Sun, The State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei-MOST) & Key Laboratory of Oral Biomedicine Ministry of Education, School & Hospital of Stomatology, Wuhan University, Wuhan 430079, China.The State Key Laboratory Breeding Base of Basic Science of Stomatology & Key Laboratory of Oral Biomedicine Ministry of Education, School & Hospital of Stomatology, State Key Laboratory of Virology, Medical Research Institute, Wuhan University, Wuhan 430071, China; Frontier Science Center for Immunology and Metabolism, Wuhan University, Wuhan 430071, China; Corresponding author: Junjie Zhang, The State Key Laboratory Breeding Base of Basic Science of Stomatology & Key Laboratory of Oral Biomedicine Ministry of Education, School & Hospital of Stomatology, State Key Laboratory of Virology, Medical Research Institute, Wuhan University, Wuhan 430071, China.Oncolytic viruses (OVs) encoding various transgenes are being evaluated for cancer immunotherapy. Diverse factors such as cytokines, immune checkpoint inhibitors, tumor-associated antigens, and T cell engagers have been exploited as transgenes. These modifications are primarily aimed to reverse the immunosuppressive tumor microenvironment. By contrast, antiviral restriction factors that inhibit the replication of OVs and result in suboptimal oncolytic activity have received far less attention. Here, we report that guanylate-binding protein 1 (GBP1) is potently induced during HSV-1 infection and restricts HSV-1 replication. Mechanistically, GBP1 remodels cytoskeletal organization to impede nuclear entry of HSV-1 genome. Previous studies have established that IpaH9.8, a bacterial E3 ubiquitin ligase, targets GBPs for proteasomal degradation. We therefore engineered an oncolytic HSV-1 to express IpaH9.8 and found that the modified OV effectively antagonized GBP1, replicated to a higher titer in vitro and showed superior antitumor activity in vivo. Our study features a strategy for improving the replication of OVs via targeting a restriction factor and achieving promising therapeutic efficacy.http://www.sciencedirect.com/science/article/pii/S2372770523000311oncolytic virusHSV-1GBP1IpaH9.8restriction factorcancer treatment |
| spellingShingle | Jun Xie Shaowei Wang Yunhong Zhong Ming Gao Xuezhang Tian Liting Zhang Dongli Pan Qingsong Qin Bing Wu Ke Lan Zhi-Jun Sun Junjie Zhang Oncolytic herpes simplex virus armed with a bacterial GBP1 degrader improves antitumor activity Molecular Therapy: Oncolytics oncolytic virus HSV-1 GBP1 IpaH9.8 restriction factor cancer treatment |
| title | Oncolytic herpes simplex virus armed with a bacterial GBP1 degrader improves antitumor activity |
| title_full | Oncolytic herpes simplex virus armed with a bacterial GBP1 degrader improves antitumor activity |
| title_fullStr | Oncolytic herpes simplex virus armed with a bacterial GBP1 degrader improves antitumor activity |
| title_full_unstemmed | Oncolytic herpes simplex virus armed with a bacterial GBP1 degrader improves antitumor activity |
| title_short | Oncolytic herpes simplex virus armed with a bacterial GBP1 degrader improves antitumor activity |
| title_sort | oncolytic herpes simplex virus armed with a bacterial gbp1 degrader improves antitumor activity |
| topic | oncolytic virus HSV-1 GBP1 IpaH9.8 restriction factor cancer treatment |
| url | http://www.sciencedirect.com/science/article/pii/S2372770523000311 |
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