Review
Introduction
The mechanism of HSV confronted the host immune response
Envelope glycoprotein
Immune evasion genes
Block dendritic cells function
Inhibition of autophagy
Inhibition of apoptosis
Genetically engineered oHSV
Gene | Protein | Function | oHSV name |
---|---|---|---|
UL27 | gB | Part of initial attachment of the virus to the cell by binding to heparan sulfate. With gH/gL, enables fusion of the envelope with the cell membrane. Down-regulation of MHC II processing pathway in CD4+ cells. | R5141; KNE |
UL44 | gC | Forms the initial attachment of the virus to the cell by binding to heparan sulfate. Inactivates serum complement proteins. | R5141 |
US6 | gD | Binds to HVeM and/or nectin-1, leading to a conformation change that initiates fusion. Down-regulates NK receptor ligand and NK-mediated lysis; inhibition of apoptosis. | R5141; R-LM249; HSV1716EGFR; KNE |
RL1 | ICP34.5 | Major neurovirulence gene. Suppression of PKR/eIF-2a signaling pathway and IFN-induced anti-viral mechanisms; Inhibits DC maturation and antigen. Presentation; Blocks MHC class II accumulation on the cell surface; Binds to Beclin-1, inhibiting autophagy. | HSV1716; R3616; OncoVexGMCSF; G47; ΔG207; DM33; |
RL2 | ICP0 | Blocks NF-κB-mediated transcription of immunomodulatory cytokines, and IRF3-induced and IRF7-induced anti-viral signaling pathways; inhibits IRF3 translocation to the nucleus; inhibits IFI16; degradation of mature DC marker (CD83). Involved in transcription of viral genes. Has ubiquitin ligase activity. Inhibits interferon response. Alters the cellular environment to promote viral replication. | R7020 (NV1020); |
UL39 | ICP6 | Major subunit of ribonucleotide reductase. Blocks TNF-a-mediated and Fas ligand-mediated apoptosis through interacting with caspase 8 and necroptosis. | hrR3; G47Δ |
UL54 | ICP27 | Inhibits cellular mRNA splicing. Recruits necessary proteins involved in viral transcription and translation. Activates cellular pathways to promote viral replication. Blocks NF-κB and IRF3 signaling pathways; blocks STAT1 activation and its translocation to the nucleus. | HF10 |
US12 | ICP47 | Down-regulates MHC class I by inhibiting TAP. | G47Δ; OncoVexGMCSF |
US11 | US11 | Binds to and is phosphorylated by PKR, preventing cellular inhibition of protein synthesis and autophagy; blocks OAS. | G47Δ |
US3 | US3 | Inhibits NF-κB activation and reduces cytokine expression, such as IL-8; inhibits induction of apoptosis; hyperphosphorylates IRF3 to block activation of RLR signaling pathway. | R7041 |
UL48 | VP16 | Initiates transcription of immediate early genes. Inhibits NF-κB activation and blocks IRF3 pathway and IFN-β production. | KM100 |
Clinical development and limitations of oHSV
oHSV name | Genetic modification | Descrption | Clinical application |
---|---|---|---|
Dlsptk | TK−(UL23) | Internal deletion within UL23 | Malignant human gliomas |
hrR3 | UL39 | Insertion of LacZ (encodes β-galactosidase) in UL39 | Pancreatic cancer; colon carcinoma; liver cancers |
HSV1716 | ICP34.5 | Deletion in both copies of ICP34.5 | Glioblastoma multiforme; anaplastic astrocytoma; oral squamous cell carcinoma |
R3616 | ICP34.5 | Deletion of two copies of ICP34.5 | Pancreatic cancer; colon carcinoma |
G207 | ICP34.5 | Deletions of two copies of the ICP34.5; insertion of an Escherichia coli LacZ | Prostate adenocarcinoma; glioblastoma; hepatocellular carcinoma; colorectal cancer |
R7020 (NV1020) | UL23, UL55, UL56, RL1, RL2, RS1 | Deletion of UL23, as well as the region encoding UL55, UL56, and one copy of RL1, RL2, and RS1 (though not the RS1 promoter) | Pancreatic cancer; colon carcinoma; bladder cancer; pleural cancer |
G47Δ | RL1, UL39, US11, US12 | Deletion of the overlapping US11 promoter/US12 region, putting expression of the normally late US11 gene under the immediate early US12 promoter | Prostate adenocarcinoma; glioblastoma; rectal cancer; nasopharyngeal carcinoma; breast cancer |
OncoVexGM-CSF | ICP34.5 and ICP47 | Deletion of two copies of ICP34.5 gene and the viral ICP47 genes; insertion of GM-CSF | Breast cancer; head and neck cancer; gastrointestinal cancers; malignant melanoma |
HF10 | UL53, UL54, UL55, UL56 | Spontaneous deletion of UL56 as well as duplication of UL53, UL54, and UL55 | Breast cancer; malignant melanoma; pancreatic cancer |
DM33 | ICP34.5 | Deletions of γ-34.5 and LAT gene | Human gliomas and glioma cell line |