Oncolytic Herpes Simplex Viral Therapy: A Stride toward Selective Targeting of Cancer Cells

Abstract

Oncolytic viral therapy, which makes use of replication-competent lytic viruses, has emerged as a promising modality to treat malignancies. It has shown meaningful outcomes in both solid tumor and hematologic malignancies. Advancements during the last decade, mainly genetic engineering of oncolytic viruses have resulted in improved specificity and efficacy of oncolytic viruses in cancer therapeutics. Oncolytic viral therapy for treating cancer with herpes simplex virus-1 has been of particular interest owing to its range of benefits like: (a) large genome and power to infiltrate in the tumor, (b) easy access to manipulation with the flexibility to insert multiple transgenes, (c) infecting majority of the malignant cell types with quick replication in the infected cells and (d) as Anti-HSV agent to terminate HSV replication. This review provides an exhaustive list of oncolytic herpes simplex virus-1 along with their genetic alterations. It also encompasses the major developments in oncolytic herpes simplex-1 viral therapy and outlines the limitations and drawbacks of oncolytic herpes simplex viral therapy.

Keywords: cancer; genetic arming; herpes simplex virus; oncolytic viral therapy; retargeted oncolytic herpes simplex virus-1.

Figure 1

Systemic delivery of oncolytic HSV-1 to the tumor cells by retargeting. (A) oHSV-1 contains the following components (1) Core, a dsDNA genome which is opaque to electrons and enfolded as a spool or a toroid. (2) Icosahedral capsid with 162 capsomers surrounding the core. Tegument proteins control the transport of DNA via channels in the capsid (3) Amorphous unstructured matrix of proteins called tegument (4) An outer envelope of lipid bilayer consisting of glycoprotein spikes. The envelope contains 13 types of glycoproteins (Zhou et al., ; Shen and Nemunaitis, 2006). (B) At first, gC and gB interact with the host cell surface glycosaminoglycan, heparan sulfate (Herold et al., , ; Spear et al., 1992). (C) Post gC and gB binding, gD interacts with host cell surface receptors, nectin-1a, nectin-1b, nectin-2a, nectin-2d, and HveA, which results in initiation of virions-cell fusion (Spear, 2004). (D) Fusion of envelope with host cell membrane and entry of viral DNA and capsid with associated tegument proteins. (E) Entry of viral DNA into the host nucleus (Herold et al., , ; Spear et al., 1992). (F) Once the viral DNA enters the nucleus through the nuclear pore host RNA polymerase II initiates Viral DNA transcription. Five immediate-early (IE) genes, ICP0, ICP4, ICP22, ICP27, and ICP47, are transcribed and translated immediately (Burton et al., 2002) stimulated by VP-16, at the same time host cell shutoff takes place. IE genes are involved in transcription and translation of other HSV genes. (G) Before the viral DNA synthesis occurs, Early (E) genes transcribe and translate viral SSBP, DNA helicase, origin binding protein, DNA polymerase and localize them into the nucleus. (H) DNA replication is origin dependent having three origin sequences. DNA replication takes place in subnuclear constructions called, replication compartments. At the end of the replication cycle, a concatemeric DNA is formed (Mocarski and Roizman, 1982). (I) Late gene transcription and translation which produces structural components of the HSV-1 virus. (J) Mature virion formation- capsid assembly and encapsidation of concatemeric DNA takes place by systematic cleavage of the concatemeric DNA. Maturation and release of virions is done through Golgi apparatus (egress). (K) The fully mature HSV-1 virus is then released from secretory vesicles (Shen and Nemunaitis, 2006).