In Vivo Behavior of Genetically Engineered Herpes Simplex Viruses R7017 and R7020: Construction and Evaluation in Rodents

Abstract

The herpes simplex virus (HSV) recombinant R7017 was constructed from HSV-1 (strain F) by deleting a portion of the thymidine kinase (tk) gene and by replacing the sequences representing the internal inverted repeats and adjacent genes in the L component with a fragment of the HSV-2 genome encoding the glycoproteins G, D, I, and a portion of E. In addition, the R7020 recombinant contains an HSV-1 DNA fragment encoding the tk gene fused to the alpha 4 gene promoter. The results of studies in mice, guinea pigs, and rabbits were as follows: Both recombinants remained unchanged after nine serial, intracerebral passages in mice; the recombinants could not be differentiated with respect to attenuation in mice injected intracerebrally, in vaginally infected guinea pigs, and in rabbits inoculated on the scarified cornea. Given intradermally or intramuscularly, the recombinants prevented severe infections by virulent challenge viruses, and R7020 established latent infections (at a low frequency) in all species tested, whereas latent R7017 virus was detected in rabbits only.

Enhancement of replication of genetically engineered herpes simplex viruses by ionizing radiation: a new paradigm for destruction of therapeutically intractable tumors

“…21 Therefore the possibility existed that GADD34 induced following DNA damage by ionizing radiation complemented R3616 and allowed a higher level of viral replication. 22 To determine whether the effects of irradiation were specific for ␥ 1 34.5 − R3616, the experiment was repeated with R7020, another genetically engineered attenuated virus. 22 Figure 3b shows that the yields of R7020 from tumors were higher than those of R3616 as would be expected since R7020 is less attenuated.…”

“…22 To determine whether the effects of irradiation were specific for ␥ 1 34.5 − R3616, the experiment was repeated with R7020, another genetically engineered attenuated virus. 22 Figure 3b shows that the yields of R7020 from tumors were higher than those of R3616 as would be expected since R7020 is less attenuated. In addition, the yields of virus from irradiated tumors were higher than those from nonirradiated tumors.…”

“…3 In the genetically engineered R7020 virus U L 24, U L 55 and U L 56, and one set of inverted repeats each encoding one copy of the genes ␣0, ␥ 1 34.5, ORF P and ␣4, was replaced by a DNA fragment derived from HSV-2 strain G encoding glycoproteins G, J, D and I. 22 Virus titers were determined on Vero cells as previously described. 12,21 Tumor regression studies U-87MG cells in amounts of 1 × 10 7 cells per mouse were suspended in sterile phosphate-buffered saline and injected subcutaneously into the right hind limb of a 5-to 6-week-old nude mouse and grown to 200 mm 3 (Fredrickson Cancer Research Institute, Bethesda, MD, USA).…”

Replication-competent herpes simplex vectors: design and applications

“…[8][9][10][11] The first attenuated HSV virus to be constructed and analyzed as a viral vaccine in humans was the NV1020 (formerly R7020) strain. 12,13 This virus, based on HSV-1 strain F, has a portion of the unique short region of the viral genome encoding glycoproteins G, D, I and E, replaced by the homologous region from HSV-2, and possesses one copy of ICP4. This virus was very strongly attenuated in rodents and primates.…”

Widespread intratumoral virus distribution with fractionated injection enables local control of large human rhabdomyosarcoma xenografts by oncolytic herpes simplex viruses

“…16,17 A number of different HSV mutants have been engineered to selectively replicate in tumor cells based on deletions of critical genetic functions that are dispensable for viral replication in cancer cells (for reviews, see Varghese et al 18 and Arceci and Cripe 19 ). For example, NV1020 20 and NV1066 21 are deleted for one copy of the diploid ''neurovirulence'' gene encoding ICP34.5. Viral infection activates the doublestranded RNA inducible protein kinase (PKR) pathway to terminate protein synthesis and prevent viral replication.…”