Arbovirus and Gene Therapy

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In addition to gene transfer, several arboviruses can be used for novel gene therapy. Semliki Forest virus is the one that is frequently used for gene therapy. The CNS gene therapy by Semliki Forest virus is widely researched. Tuittila et al. noted that induction of proinflammatory cytokine mRNA in the CNS by SFV infection seemed to correlate with the rate of viral replication and was not importantly influenced by the virus envelope or nonstructural protein primary structure Semliki Forest virus [34]. They said that the outcomes had relevance for development of CNS gene therapy vectors as SFV4 and A774 display differences in CNS infection characteristics [34]. However, Graham et al. reported that the current SFV1 vector system was limited in its property for CNS gene therapy by neurotoxicity [35]. In addition to CNS gene therapy, the use of Semliki Forest virus in cancer gene therapy is widely mentioned in the literature. It was observed that that recombinant particles, naked RNA and plasmid DNA containing Semliki Forest virus replicons, could demonstrate a strong immune response against recombinantly expressed proteins, which had shown preventive action against tumor challenges [36]. Intratumoural injection of Semliki Forest virus particles had led to tumor regression [36]. Colmenero et al. reported that immunotherapy with recombinant Semliki Forest virus -replicons expressing the P815A tumor antigen or interleukin-12 (IL-12) could lead to tumor regression [37]. Murphy et al. reported an inhibition of human lung cancer cell growth by apoptosis induction using Semliki Forest virus recombinant particles [38]. In their study [38], direct injection of rSFV into H358a tumors subcutaneously implanted as xenografts in nu/nu mice inhibited tumor growth, and in some studied subjects caused absolute regression [38]. It is concluded that tumor growth suppression induced by rSFV was owing to apoptosis induction and that the vector has an inherent cell death-promoting and antitumor activity [38]. Asselin-Paturel et al. reported that transfer of the murine interleukin-12 gene in vivo by a Semliki Forest virus vector could lead to B16 tumor regression through inhibition of tumor blood vessel formation monitored by Doppler ultrasonography [39]. In 2007, Lyons et al. reported a similar observation in their study that active immunization with rSFV particles coding for VEGFR-2 could break immunological tolerance and could potentially be applied as part of a new treatment for cancer [40]. They reported that co-immunization of mice with rSFV particles encoding vascular endothelial growth factor receptor-2 (VEGFR-2) and IL-12 completely abrogated both the antibody result and the antitumor activity [40]. Prevention of angiogenesis by a Semliki Forest virus vector expressing VEGFR-2 reduces tumour growth and metastasis in mice is proposed [41]. This result is similar to another report by Chikkanna-Gowda et al. in 2005 [41]. Indeed, the induction of a therapeutic antitumor immunological response by intratumoral injection of genetically engineered Semliki Forest virus to cause IL-12 was published by Yamanaka et al. since 2000 [42].

Sindbis virus is also proposed for its effectiveness in gene therapy for several cancers

[43]. Hay noted that a recent report demonstrates that the Sindbis virus had significant properties in three challenging areas of gene therapy - specificity, efficacy and delivery, suggesting that Sindbis had the feasibility to become a good gene therapy vector for cancer therapy [43]. Cancer immunotherapy by Sindbis virus is the new way in the cancer treatment. Cheng et al. recently used the replication-defective vaccine vector Sindbis virus replicon particles from a modern packaging cell line (PCL) to contract Sindbis virus replicon particles encoding calreticulin (CRT) linked to a model tumor antigen, HPV16 E7 protein [43]. Cheng et al. created a recombinant Sindbis virus -based replicon particle encoding VP22 linked to a model tumor antigen, human papillomavirus type 16 (HPV-16) E7, making use of a stable SIN PCL [44]. According to this study, Sindbis virus replicon particles encoding calreticulin linked to a tumor antigen caused long-term tumor-specific immunity [44]. Cheng et al. concluded that the CRT strategy used in the context of SIN replicon particles facilitated the generation of a significantly effective vaccine for cancer prophylaxis and immunotherapy

[44]. Cheng et al. also indicated that the VP22, a herpes simplex virus type 1 (HSV-1) tegument protein, strategy applied in the context of Sindbis virus replicon particles might enhance the generation of a highly effective vaccine for widespread immunization [45]. Zhnag et al. reasoned that Sindbis-virus-based vectors might be good for gibbon ape leukemia virus envelope glycoprotein (GALV.fus) gene transfer because high-titer stocks can easily be caused in hamster cells and Sindbis virus efficiently infects human tumor cells through the high-affinity 67 kDa laminin receptor [46]. They reported that Sindbis vectors expressing GALV.fus could be packaged into contagious viral particles to high titer, exhibited potent bystander cytopathic activity and were active against U87 glioma xenografts [28]. They concluded that Sindbis-virus-based replicons was efficient vector systems for delivery and expression of fusogenic membrane glycoproteins [46]. In 1998, Swai and Meruelo explored the possibility of designing a Sindbis virus vector that could attack human choriocarcinoma cells via ligand-receptor interaction [47]. In this study, the hCG-envelope chimeric virus vector had minimal infectivities against BHK cells and human cancer cells which did not pose LH/CG receptors on their surface [47]. Swai and Meruelo proposed that the chimeric Sindbis virus vector may bring a novel approach for gene therapy of gestational trophoblast disease and placental dysfunction [47]. Bergman attempted to construct a virus that targeted specifically to breast cancer cells [48]. In their attempt, nonreplicating and replicating pseudotype Vesicular stomatitis virus (VSV) were constructed whose only surface glycoprotein (gp) was a Sindbis gp, called Sindbis-ZZ, modified to severely decrease its native binding function and to contain the Fc-binding domain of Staphylococcus aureus protein A [48]. Bergman et al. reported that vesicular stomatitis virus expressing a chimeric Sindbis glycoprotein containing an Fc antibody binding domain could attack to Her2/neu overexpressing breast cancer cells [48]. This work demonstrates the ability to easily create, directly from plasmid components, an oncolytic replicating VSV with a restricted host cell range [48]. Morizono et al. reported successful targeting in a living animal through intravenous injection of a lentiviral vector pseudotyped with a adapted chimeric Sindbis virus envelope (termed m168) [49]. They found that m168 pseudotypes had high titer and high targeting specificity and, unlike other retroviral pseudotypes, had low nonspecific infectivity in hepatic and spleen [49]. According to this study, human P-glycoprotein was ectopically demonstrated on the surface of melanoma cells and attacked by the m168 pseudotyped lentiviral vector conjugated with antibody specific for P-glycoprotein. m168 pseudotypes successfully attacked metastatic melanoma cells growing in the lung after systemic administration by tail vein injection [50].

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