Herpes simplex virus 1 as an oncolytic viral therapy for refractory cancers

Abstract

The need for efficacious and non-toxic cancer therapies is paramount. Oncolytic viruses (OVs) are showing great promise and are introducing new possibilities in cancer treatment with their ability to selectively infect tumor cells and trigger antitumor immune responses. Herpes Simplex Virus 1 (HSV-1) is a commonly selected OV candidate due to its large genome, relative safety profile, and ability to infect a variety of cell types. Talimogene laherparevec (T-VEC) is an HSV-1-derived OV variant and the first and only OV therapy currently approved for clinical use by the United States Food and Drug Administration (FDA). This review provides a concise description of HSV-1 as an OV candidate and the genomic organization of T-VEC. Furthermore, this review focuses on the advantages and limitations in the use of T-VEC compared to other HSV-1 OV variants currently in clinical trials. In addition, approaches for future directions of HSV-1 OVs as cancer therapy is discussed.

Keywords: Herpes simplex virus 1; T-VEC; cancer; oncolytic virus; virotherapy.

Figure 1

Herpes Simplex Virus-1 (HSV-1) Life Cycle: Adsorption and fusion of HSV-1 to its target cell is initiated by viral glycoprotein D (gD) to cell specific gD receptors (1). Fusion of the viral envelope with cell membrane allows for capsid entry into the cytoplasm and release of tegument proteins (2). The naked viral capsid is transported (3) to nuclear pore complexes in the nuclear envelope (4), through which the viral genome is extruded into the nucleus (5). The linear viral genome is circularized (6). Herpes viruses have three rounds of transcription: immediate early (α-genes) (7), early (β-genes) (8), and late (γ-genes) (9). Translation of the structural proteins from γ- transcripts occurs only after the initiation of viral genome replication, which is dependent on β-proteins. Viral transcripts leave the nucleus to be translated (10) in either the cytoplasm or in the context of the endoplasmic reticulum (ER). Capsids are assembled in the nucleus, encasing the viral genome in an icosahedral protein coat (11). The newly generated viral capsid acquires an envelope by budding into the inner nuclear membrane (12). The completed virus translocates through the ER and matures in the Golgi apparatus prior to exiting the cell by exocytosis (13). Created with BioRender.com.

Figure 2

HSV-1 Genomic map and oncolytic virus modifications (A) The HSV-1 genome has two covalently joined segments long (L) and short (S) each of which has a unique sequence (U_L and U_S) flanked by a pair of repeat sequences, the terminal and internal long repeats (TL_L, IR_L, TR_S and IR_S). There is also a 400 base pair terminal repeat at each end of the genome and internally at the joint between the L and S segments which is called (a) Genes are coded according to functional group: blue- structural; red- replication; green- virulence. (B) Oncolytic viruses mentioned in the paper. Deleted viral genes are indicated as (-) while transgenes or viral genes that have been inserted are in bold and indicated by (+). Diagram prepared with DRAWIO.