Naturally occurring oncolytic viruses are live, replication-proficient viruses that specifically infect human cancer cells while sparing normal cell counterparts. Since the eradication of smallpox in the 1970s with the aid of vaccinia viruses, the vaccinia viruses and other genera of poxviruses have shown various degrees of safety and efficacy in pre-clinical or clinical application for human anti-cancer therapeutics. Furthermore, we have recently discovered that cellular tumor suppressor genes are important in determining poxviral oncolytic tropism. Since carcinogenesis is a multi-step process involving accumulation of both oncogene and tumor suppressor gene abnormalities, it is interesting that poxvirus can exploit abnormal cellular tumor suppressor signaling for its oncolytic specificity and efficacy. Many tumor suppressor genes such as p53, ATM, and RB are known to play important roles in genomic fidelity/maintenance. Thus, tumor suppressor gene abnormality could affect host genomic integrity and likely disrupt intact antiviral networks due to accumulation of genetic defects, which would in turn result in oncolytic virus susceptibility. This review outlines the characteristics of oncolytic poxvirus strains, including vaccinia, myxoma, and squirrelpox virus, recent progress in elucidating the molecular connection between oncogene/tumor suppressor gene abnormalities and poxviral oncolytic tropism, and the associated preclinical/clinical implications. I would also like to propose future directions in the utility of poxviruses for oncolytic virotherapy.

Z-FA-FMK is a very effective viral inhibitor that can prevent reovirus replication in vitro and reovirus-mediated myocarditis, as well as reovirus-mediated oncolysis, in vivo. A potential application of this drug for inhibition of reovirus infection is suggested.

Hantaanvirus (HTNV) is the prototype of the genus Hantavirus, which belongs to the family Bunyaviridae. Hantaviruses are carried and transmitted by rodents and are known to cause two serious disease syndromes in humans i.e., hemorrhagic fever with renal syndrome (HFRS) and the hantavirus pulmonary syndrome (HPS). HTNV is an enveloped virus that contains a tripartite genome consisting of three negative-sense RNA segments (L, M, S), and the S and M segment of HTNV, respectively, encode the viral nucleocapsid protein (NP) and envelope glycoproteins. Possible phosphorylation motifs of casein kinase II (CKII) and protein kinase C (PKC) were identified in HTNV NP through bioinformatics searches. Sucrose gradient SDS-PAGE analysis indicated that dephosphorylated HTNV NP migrated faster than non-dephosphorylated NP, suggesting that HTNV NP is phosphorylated in infected Vero E6 cells. Immunoblot anaylsis of HTNV particles with anti-phosphoserine antibody and anti-phosphothreonine antibody after immunoprecipitation showed that viral particles are readily phosphorylated at threonine residues. In vitro kinase assay further showed that HTNV NP is phosphorylated by CK II, but not by PKC. Full length or truncated HTNV NPs expressed in E. coli were phosphorylated in vitro by CKII suggesting that phosphorylation may occur in vivo at multiple sites. Site specific mutagenesis studies suggest that HTNV NP phosphorylation might occur at unknown sites excluding the site-directly mutagenized locations. Taken together, HTNV NP can be phosphorylated mainly at threonine residues in vivo by CK II treatment.

Nucleotide and amino acid substitution pattern in vif gene of the Korean clade of HIV-1 isolated from Koreans were analyzed using consensus sequences. At nucleotide level, transition/transversion substitution ratio was 1.88, and nonsynonymous/synonymous substitution ratio was 2.67, suggesting a divergent evolution in the Korean clade. At amino acid level, there were 17 substitutions and G-->E substitution at position 37 may be responsible for change in predicted secondary structure.

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Abstract. The tumor necrosis factor (TNF)-related apoptosisinducing ligand (TRAIL) has been used to treat a variety of cancer cells. However, since some gastric cancer cells are resistant to TRAIL, we explored whether reovirus induces cytolysis in TRAIL-resistant gastric cancer cells. We found that TRAIL-resistant SNU-216 gastric cancer cells were susceptible to apoptosis by reovirus infection. Furthermore, co-treatment with reovirus and TRAIL accelerated apoptosis of SNU-216 cells by down-regulation of Akt activation as assessed by a very low activation of Akt in TRAIL-sensitive SNU-668 gastric cancer cells. Inhibition of Akt signaling with wortmannin or suppression of Akt expression with sh-Akt lentivirus promoted reovirusmediated apoptosis of SNU-216 gastric cancer cells. Reovirus infection also down-regulates the activation of signaling molecules such as Ras and ERK involved in cell proliferation and survival but not the activation of p38 MAPK involved in cellular stress. In addition, the cotreatment with reovirus and TRAIL resulted in cleavage of caspase-8, caspase-9 and Bid, leading to a decrease in the mitochondrial membrane potential, indicating that reovirus may utilize the mitochondrial intrinsic apoptotic pathway in TRAIL-resistant SNU-216 gastric cancer cells. Accordingly, we first demonstrate that reovirus infection down-regulates Akt activation, leading to apoptosis of TRAIL-resistant gastric cancer cells. IntroductionTNF-related apoptosis-inducing ligand (TRAIL), which belongs to the family of TNF, induces apoptosis in a wide variety of tumor cells in vitro and in vivo but does not cause toxicity in a majority of normal cells (1,2). Thus, TRAIL has been suggested as a novel anti-cancer therapeutic drug. The TRAIL-mediated apoptotic signal is transduced through the cell surface death receptor (DR)s such as DR4/TRAIL-R1 and DR5/TRAIL-R2 (3,4). Detailed studies have shown that TRAIL triggers apoptosis by recruiting the initiator procaspase-8 through the adaptor protein FADD. Caspase-8 can directly activate downstream effector caspases including procaspase-3, -6 and -7, or cleave Bid, which triggers mitochondrial damage (5,6). However, different types of cancer cells appear to differ in their sensitivity to TRAIL treatment. Recent studies have reported that prostate and renal cancer cells are resistant to TRAIL treatment due to an up-regulation of Akt activity and enhanced FLIP expression (7,8). In addition, it has been reported that the resistance of certain gastric cancer cells to TRAIL-induced apoptosis can be explained by the up-regulation of FLIPs by Akt, indicating that Akt is a crucial component in the regulation of TRAIL-induced apoptosis (9). In contrast, other studies failed to demonstrate a link between FLIP expression and TRAIL resistance using melanoma and Burkitt's lymphoma (10,11).The human reovirus is a ubiquitous, non-enveloped virus with 10 segments of double-stranded RNA (12). The virus infection is usually restricted to the upper respiratory and gastrointestinal tracts and is often...

Naturally occurring reoviruses are live replication-proficient viruses that specifically infect human cancer cells while sparing their normal counterpart. Since the discovery of reoviruses in 1950s, they have shown various degrees of safety and efficacy in pre-clinical or clinical applications for human anti-cancer therapeutics. I have recently discovered that cellular tumor suppressor genes are also important in determining reoviral tropism. Carcinogenesis is a multi-step process involving the accumulation of both oncogene and tumor suppressor gene abnormalities. Reoviruses can exploit abnormal cellular tumor suppressor signaling for their oncolytic specificity and efficacy. Many tumor suppressor genes such as p53, ataxia telangiectasia mutated (ATM), and retinoblastoma associated (RB) are known to play important roles in genomic fidelity/maintenance. Thus, a tumor suppressor gene abnormality could affect host genomic integrity and likely disrupt intact antiviral networks due to the accumulation of genetic defects which in turn could result in oncolytic reovirus susceptibility. This review outlines the discovery of oncolytic reovirus strains, recent progresses in elucidating the molecular connection between oncogene/tumor suppressor gene abnormalities and reoviral oncotropism, and their clinical implications. Future directions in the utility of reovirus virotherapy is also proposed in this review. [BMB Reports 2015; 48(8): 454-460]

Naturally occurring reoviruses are live replication-proficient viruses specifically infecting human cancer cell while sparing normal counterpart. Since the discovery of reoviruses in 1950s, reoviruses have shown various degrees of safety and efficacy in pre-clinical or clinical application for human anti-cancer therapeutics. I have recently shown that cellular tumor suppressor genes, such as p53, ATM (Ataxia telangiectasia mutated), and RB (Retinoblastoma associated), are important in determining reoviral oncotropism. Thus, it is interesting to examine whether the aberrancy of c-Myc expression, whose normal function also plays an important role in the maintenance of genomic integrity, could affect reoviral oncolytic tropism. Hs68 cells are non-tumorigenic normal cells and resistant to reoviral cytopathic effects. Importantly, I found that c-Myc overexpression in human HS68 cells effectively induced reovirus cytophatic effects compared to mock expressed cells as shown by the typical reoviral cytophathology and an increased level of caspase-3 activity. Taken together, overexpression of c-Myc could play an important role in determining reoviral oncolytic tropism.