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Microbes & Immunity Genetic therapy with HSV-1 vectors

5. Application of the HSV-1 vector HSV-1 oncolytic viral vectors rely on the unique highly
expressed enzymes TK and ribonucleoside reductase (RR)
HSV-1 has the characteristics of neurotropic cells and can in tumor cells to initiate and continuously self-replicate,
establish a stable latent state; thus, it has become a novel induce an immune killing response, and ultimately lead
viral vector for exogenous genes to enter the nervous to the disintegration and death of tumor cells. However,
system. For more than two decades, research has shown for differentiated and mature normal cells, viruses do not
that HSV-1 viral vectors have opened new paths for gene undergo self-replication even when they enter cells due
therapy, from theoretical ideas to basic research to clinical to the lack of the specific enzymes TK and RR. DlspTK
exploration. Compared with traditional gene therapy
methods and effects, the current research data and results is a recombinant HSV-1 strain lacking TK that replicates
support the application of HSV-1 vectors. in a manner dependent on a high content of TK in tumor
cells and inhibits tumor growth when inoculated into
Due to the reliable biosafety of the HSV-1 virus, three gliomas in the brains of nude mice. However, the virus
HSV-1-derived vectors were used in clinical experiments strain is still neurovirulent, and TK is the target molecule
very early, but basic research is being conducted. For of the antitumor drugs GCV and ACV; therefore, these
example, amplicon vectors are mainly used for the following two drugs cannot be used for treatment at the same
reasons: (1) experimental gene therapy for inherited time, which greatly limits the oncolytic application of
genetic diseases of the nervous system, such as movement the virus strain. hrR3 is an HSV-1 recombinant strain
disorders; (2) studies on neurodegenerative disorders that is inactivated by the insertion of the RR gene via
using experimental models of Parkinson’s disease and the LacZ gene and has therapeutic effects on rat gliomas
Alzheimer’s disease; (3) studies on neuroprotection and as well as metastatic colon and pancreatic cancers, but it
synaptic repositioning; (4) studies on brain tumors; and (5) remains neurotoxic. Recombinant HSV-1 lacking γ34.5
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studies on a series of composite functions of the nervous was found to be neurotoxic and to replicate in dividing
system caused by anxiety, sexual behavior, learning, and cells, and recombinant HSV-1 R3616 and R1716 lacking
memory in animal models. double copies of γ34.5 showed high safety in both mouse
Many different types of HSV-1-derived vectors have experiments and phase I clinical trials. R3616 is used to
also entered the preclinical stage, not only for the nervous treat gliomas and ovarian tumors. In mice, R1716 combined
system but also for muscle, heart, liver, and other tissues with chemotherapeutic agents also showed good efficacy in
that have undergone certain therapeutic studies but also the treatment of non-small cell lung cancer, breast cancer,
for individual transgenic HSV-1 vectors in the clinical malignant mesothelioma and neuroblastoma.
experimental stage. Importantly, talimogene laherparepvec The investigators subsequently developed oncolytic
has been approved by the U.S. Food and Drug viruses with multiple genetic mutations, mainly deletions
Administration for the treatment of malignant melanoma. of γ34.5, together with one or several IE genes, such as
Here, we briefly introduce the application of herpesvirus NV1020, G207, and G47∆. The NV1020 virus, which loses
vectors in oncolytic therapy, vaccine development and most of the IR region of HSV-1 while inserting multiple
chronic pain treatment.
envelope glycoprotein-encoding genes of HSV-2 into this
5.1. Oncolytic therapy locus and retaining a single copy of γ34.5, has now entered
Phase II clinical trials. NV1023, modified from NV1020,
Genetically altered replicative viral vectors have been used has a certain inhibitory effect on prostate cancer, head and
in cancer therapy and gene delivery. These highly attenuated neck squamous cell carcinoma, and colon cancer, and the
viruses can selectively invade and kill tumor cells through fusion ability of OncSyn and OncdSyn can also effectively
a process known as oncolytic virotherapy, which has been inhibit the growth of breast cancer in mice. The G207
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extensively studied over the past decade. HSV, adenovirus, virus lacks a double copy of γ34.5 on the basis of hrR3, is
and vaccinia virus have been engineered for cancer treatment. safe, is very sensitive to GCV and ACV, and can effectively
As a class of oncolytic viral vectors, HSV-1-derived viruses treat malignant gliomas in clinical Ib/II. 62,63
have several obvious advantages: (1) they can infect many
types of tumor cells; (2) the DNA genome is large and The G47∆ virus was engineered by knocking out
can be easily modified by modern DNA recombination ICP47 on the basis of G207. ICP47 is associated with
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technology, recombining and adding exogenous therapeutic Type I MHC-mediated antigen presentation in infected
genes, thereby strengthening the oncolytic properties of the cells, and ICP47 deletion induces robust immune effects
virus; (3) some viruses have begun to be clinically applied and kills infected cells. Knockdown of the ICP47 gene
to human tumors such as gliomas and have good biosafety; was accompanied by knockdown of the promoter of the
and (4) they have effective drug control. latter US11 late gene, which was directly controlled by the

Volume 2 Issue 2 (2025) 25 doi: 10.36922/mi.7947