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Updated: Jul 29, 2025
Growth, Purification, and Titration of Oncolytic Herpes Simplex Virus
Published on: May 13, 2021
Oncolytic herpes simplex virus armed with a bacterial GBP1 degrader improves antitumor activity
Jun Xie1,2, Shaowei Wang1,2, Yunhong Zhong1,2
1The 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.
Abstract:
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.
Insights
Researchers engineered an oncolytic virus (OV) to overcome antiviral defenses. By targeting guanylate-binding protein 1 (GBP1), the modified OV showed enhanced replication and superior antitumor activity in cancer immunotherapy.
Area of Science:
- Virology
- Immunology
- Oncolytic Virus Therapy
Background:
- Oncolytic viruses (OVs) are explored for cancer immunotherapy, often engineered with transgenes to enhance anti-tumor effects.
- Antiviral restriction factors, like guanylate-binding protein 1 (GBP1), can limit OV replication and efficacy, receiving less attention than transgene strategies.
- GBP1 restricts herpes simplex virus type 1 (HSV-1) replication by disrupting cytoskeletal organization, hindering viral genome entry into the nucleus.
Purpose of the Study:
- To investigate the role of GBP1 as a restriction factor against HSV-1 replication.
- To engineer an OV that can antagonize GBP1 to improve its oncolytic potential.
- To evaluate the efficacy of the engineered OV in vitro and in vivo.
Main Methods:
- Investigated GBP1 induction and its effect on HSV-1 replication.
- Utilized a bacterial E3 ubiquitin ligase, IpaH9.8, known to target GBP1 for degradation.
- Engineered an oncolytic HSV-1 to express IpaH9.8 to antagonize GBP1.
- Assessed viral replication in vitro and antitumor activity in vivo.
Main Results:
- GBP1 was found to be potently induced during HSV-1 infection, restricting viral replication.
- Engineered OV expressing IpaH9.8 effectively antagonized GBP1.
- The modified OV exhibited significantly higher replication titers in vitro.
- Superior antitumor efficacy was observed in vivo with the engineered OV.
Conclusions:
- Targeting host antiviral restriction factors, such as GBP1, is a viable strategy to enhance OV replication and therapeutic efficacy.
- Engineering OVs to express bacterial effectors like IpaH9.8 can overcome host defenses.
- This approach offers a promising avenue for improving oncolytic virotherapy for cancer treatment.
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