image: (i) Direct fusion pathway: HSV-1 initially attaches to the host cell surface via the binding of gC and/or gB to heparan sulfate proteoglycans (HSPGs). This attachment is followed by the binding of gD to its specific receptors, such as nectin-1. The receptor binding induces a conformational change in gD, transitioning it from a self-inhibited state to an active conformation that exposes its pre-fusion domain (PFD). This activation signal is transmitted to the gH/gL heterodimer. Concurrently, the gH/gL complex binds to integrin receptors on the host cell surface, causing the dissociation of gL from the complex and activating gH. Activated gH interacts with the cytoplasmic domain (CTD) of gB, triggering a conformational shift in gB from its pre-fusion to post-fusion state. This shift facilitates the fusion of the viral envelope with the host cell membrane, releasing the viral DNA into the host nucleus to initiate replication.
(ii) Endocytic pathway: In some cell types, the gH/gL complex activates integrin receptors, promoting viral endocytosis through signaling via the C-terminal tail of the integrin β subunit. Within the acidic environment of the endosome, gB is activated, facilitating the fusion of the viral envelope with the endosomal membrane. This process releases the viral capsid and tegument proteins into the cytoplasm. The viral DNA is subsequently transported to the nucleus, where it initiates transcription and replication. The figure was created with BioRender.com
Credit: Yufang Zou, Juan Tao, Yingzheng Gao, Jixuan Wang, Pengfei Wang, Jingyuan Yan, Zuqing Nie, Dewei Jiang, Xinwei Huang
In a recent review in Genes & Diseases, researchers from the Second Affiliated Hospital of Kunming Medical College, Kunming Institute of Zoology, Chinese Academy of Sciences, and University of the Chinese Academy of Sciences explore the molecular mechanisms underlying HSV glycoprotein-mediated cell entry, the recent advances in receptor-retargeted oHSV-1 engineering, while highlighting the challenges and future directions in the development of oncolytic HSV-based therapies.
Viral entry into the cells differs with cell types. Differences in receptor expression levels and affinities across cell types determine the specific entry pathways used by HSV-1. This review describes the mechanisms of HSV-1 cell entry, including (i) the direct virion-cell fusion pathway, (ii) the endocytic pathway, and (iii) pathways mediated by specific glycoproteins and their receptors (e.g., glycoprotein C, glycoprotein D, the HSV fusogen gB, and glycoprotein gH/gL).
The review then details the strategies employed for the tropism retargeting of oHSV-1. Conditional replication of oHSV-1 limits viral replication in non-replicating cells while enabling replication in tumor cells to achieve targeted tumor destruction. This is achieved by genetically modifying the virus, primarily by inserting mutations or deletions in viral replication regulatory genes, such as UL39 and UL23, which endow oHSV-1 with tumor-specific cytotoxicity through various mechanisms. Similarly, multi-gene knockout and transcriptional reprogramming are other strategies to engineer oHSV-1 with conditional replication, selective tumor targeting, and safety.
An alternative approach to oHSV-1 retargeting involves redirecting viral tropism to cancer-specific receptors while detargeting natural receptors, enhancing cancer specificity without requiring gene deletions. This strategy involves modifying glycoproteins gD, gH, and gB, which play a major role in viral entry. Previous reports have reported the successful retargeting against a range of tumor-associated receptors, including IL13Rα2, uPAR, GFRα1, HER2, EGFR, PSMA, and EGFRvIII, enabling selective infection of breast cancer, ovarian cancer, and brain tumor cells.
Despite progress in engineering tumor-targeted oHSV-1 with improved specificity and efficacy, off-target effects and alternative entry routes remain challenges, necessitating synergistic modifications across multiple glycoproteins. Future development must focus on integrating advanced gene editing and immunotherapy, alongside dual-layered regulation—combining glycoprotein-based retargeting with tumor-specific replication control—to enhance safety, specificity, and efficacy against metastatic cancers.
In conclusion, integrating innovative glycoprotein engineering, advanced gene editing, and immunotherapy may help bridge the gap between experimental therapeutics and clinical application, positioning oHSV-based therapies as a potential candidate for treating metastatic and refractory cancers.
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