A neuroattenuated ICP34.5-deficient herpes simplex virus type 1 replicates in ependymal cells of the murine central nervous system.

Kesari, Santosh; Lasner, Todd M.; Balsara, Keki R.; Randazzo, B.; Lee, V. M.-Y.; Trojanowski, John Q.; Fraser, Nigel W.

doi:10.1099/0022-1317-79-3-525

Cited by 39 publications

(32 citation statements)

References 42 publications

(31 reference statements)

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“…Contrary to their previous findings 28 Kesari et al showed that 1716 can replicate in ependymal cells 29 and that intraventricular injection of high doses in nude mice is followed by death in some animals. 30 They concluded that these studies should serve as a warning for the use of 1716 in immunosuppressed humans.…”

Section: Discussioncontrasting

confidence: 57%

Toxicity evaluation of replication-competent herpes simplex virus (ICP 34.5 null mutant 1716) in patients with recurrent malignant glioma

et al. 2000

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Section: Discussioncontrasting

confidence: 57%

Toxicity evaluation of replication-competent herpes simplex virus (ICP 34.5 null mutant 1716) in patients with recurrent malignant glioma

et al. 2000

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“…When R3616 was injected into the striatum of mice, virus spread to the ventricles, presumably through leakage into the CSF, so that within 7 days the ependymal cells in the lateral ventricles had disappeared (48). Direct inoculation of 1716 into the ventricles of BALB/c mice also led to a loss of ependymal cells and hydrocephalus but no mortality (34). When 1716 was injected into the ventricles of nude mice, it caused high mortality even at low doses (10 3 PFU) (41).…”

Section: Discussionmentioning

confidence: 99%

Attenuated, Replication-Competent Herpes Simplex Virus Type 1 Mutant G207: Safety Evaluation in Mice

Sundaresan

Hunter

Martuza

et al. 2000

J Virol

137

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Herpes simplex virus type 1 (HSV-1) mutants that are attenuated for neurovirulence are being used for the treatment of cancer. We have examined the safety of G207, a multimutated replication-competent HSV-1 vector, in mice. BALB/c mice inoculated intracerebrally or intracerebroventricularly with 10 7 PFU of G207 survived for over 20 weeks with no apparent symptoms of disease. In contrast, over 80% of animals inoculated intracerebrally with 1.5 ؋ 10 3 PFU of HSV-1 wild-type strain KOS and 50% of animals inoculated intracerebroventricularly with 10 4 PFU of wild-type strain F died within 10 days. Similarly, after intrahepatic inoculation of G207 (3 ؋ 10 7 PFU) all animals survived for over 10 weeks, whereas no animals survived for even 1 week after inoculation with 10 6 PFU of KOS. After intracerebroventricular inoculation, LacZ expression was initially observed in the cells lining the ventricles and subarachnoid space; expression decreased until almost absent within 5 days postinfection, with no apparent loss of ependymal cells. G207 DNA could be detected by PCR in the brains of mice 8 weeks after intracerebral inoculation; however, no infectious virus could be detected after 2 days. As a model for latent HSV in the brain, we used survivors of an intracerebral inoculation of HSV-1 KOS at the 50% lethal dose. Inoculation of a high dose of G207 at the same stereotactic coordinates did not result in reactivation of detectable infectious virus or symptoms of disease. We conclude that G207 is safe at or above doses that were efficacious in mouse tumor studies.Herpes simplex virus type 1 (HSV-1) is a neurotropic DNA virus which infects a wide range of cell types in different animals. Natural infections either follow a lytic, replicative cycle or establish latency. Latency is characterized by the long-term persistence of viral DNA in latently infected neurons, the lack of infectious or replicating virus, the lack of viral gene expression except for the latency-associated transcripts (LATs), and in some situations episodic reactivation of infectious virus (74). In humans, the natural host, HSV-1 causes a number of diseases, including gingivostomatitis and pharyngitis after primary oral-facial infection, recurrent herpes labialis, genital herpes, keratitis after eye infection, disseminated visceral infections in immunocompromised patients, hepatitis, and encephalitis after spread to the central nervous system (CNS) (13).HSV encephalitis is the most common CNS viral infection, occurring in two to three persons per million (13). Brain pathology is usually localized to the temporal lobe and limbic system, with asymmetric necrotizing encephalitis, inflammation, and hemorrhage (19, 33). The majority of cases of encephalitis occur in patients with recurrent HSV who are seropositive at onset of disease. Even with acyclovir therapy, mortality is about 20%, and about 20% of survivors have longterm morbidity, including cognitive abnormalities (23, 51).A number of animal models of HSV encephalitis involving spread from peripheral in...

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“…[161][162][163] Therefore, additional deletions or alterations have been made to the HSV-1 mutant strains described above to further increase the safety margin of the vectors as well as to decrease the likelihood of reversion to wild type. 164 These strains are often referred to as the second-generation viruses to distinct them from the strains that contain deletions of a single viral gene.…”

Section: Hsv-1 For Cancer Treatment Y Shen and J Nemunaitismentioning

confidence: 99%

Herpes simplex virus 1 (HSV-1) for cancer treatment

2006

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Cancer remains a serious threat to human health, causing over 500 000 deaths each year in US alone, exceeded only by heart diseases. Many new technologies are being developed to fight cancer, among which are gene therapies and oncolytic virotherapies. Herpes simplex virus type 1 (HSV-1) is a neurotropic DNA virus with many favorable properties both as a delivery vector for cancer therapeutic genes and as a backbone for oncolytic viruses. Herpes simplex virus type 1 is highly infectious, so HSV-1 vectors are efficient vehicles for the delivery of exogenous genetic materials to cells. The inherent cytotoxicity of this virus, if harnessed and made to be selective by genetic manipulations, makes this virus a good candidate for developing viral oncolytic approach. Furthermore, its large genome size, ability to infect cells with a high degree of efficiency, and the presence of an inherent replication controlling mechanism, the thymidine kinase gene, add to its potential capabilities. This review briefly summarizes the biology of HSV-1, examines various strategies that have been used to genetically modify the virus, and discusses preclinical as well as clinical results of the HSV-1-derived vectors in cancer treatment.

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A neuroattenuated ICP34.5-deficient herpes simplex virus type 1 replicates in ependymal cells of the murine central nervous system.

Cited by 39 publications

References 42 publications

Toxicity evaluation of replication-competent herpes simplex virus (ICP 34.5 null mutant 1716) in patients with recurrent malignant glioma

Toxicity evaluation of replication-competent herpes simplex virus (ICP 34.5 null mutant 1716) in patients with recurrent malignant glioma

Attenuated, Replication-Competent Herpes Simplex Virus Type 1 Mutant G207: Safety Evaluation in Mice

Herpes simplex virus 1 (HSV-1) for cancer treatment

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