SV and derived SV vectors have been extensively studied in the United States. The SV replicon system was the first of the three alphavirus replicon systems to be reported, in 1989 by Xiong et al. (3). As originally described, the engineered SV replicon RNA was packaged by tranfection of in vitro-transcribed RNA into BHK cells that were then infected with wild-type SV. As the replicon RNA contained the packaging signal, it was packaged in a small percentage of virions essentially competing with wild-type SV genomic RNA for encapsidation and assembly into infectious particles. The efficiency of producing particles containing replicon RNA encoding heterologous protein was estimated at approx 10%. A packaging system analogous to that described above for SFV replicons utilizing two in vitro-transcribed RNAs, one encoding the structural proteins and the other the engineered "genomic" RNA, was described in 1993 (76). However, this system still resulted in significant contamination of the replicon preparations with replication-competent virions capable of propagating an active SV infection (79,113,114). Use of nonredundant split RNA helper system, as used for VEE replicons, was described in 1997 but not used for antitumor immunotherapy (115). The host tissue receptivity for SV replicons includes fibroblasts and skeletal muscle (6), neuronal cells (116), and cardiomyocytes (31). In contrast to SFV and VEE, SV does not have significant tropism for lymphoid tissues unless mutations are introduced into the envelope glycoproteins (117-121). Comparisons of various alphavirus-derived expression systems demonstrate SV to have equivalent or more robust heterologous protein expression, compared to SFV (85,114,118,122), and SV may have other as yet undefined characteristics that result in more robust antitumor immune responses (85). SV replicon RNA-based polynucleotide immunization or derived hybrid polynucleotide vectors have been or are being evaluated for the capacity to elicit or enhance antitumor immunity in four model systems (see Table 3), with multiple modifications in one model system. SV replicons per se have not been reported in antitumor immunotherapeutic strategies. One model system, the LacZ model antigen, has been discussed above (85). Work in one model system, CEA, was funded by NIH in 2001 (Conroy, R.M., University of Alabama, CRISP Database), but there have been no published reports or presentations on this work to date, thus it will not be discussed further.
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