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GADD34 is expressed in the ischaemic brain and reverses protein synthesis shutdown. Consequently, GADD34 could have neuroprotective potential in stroke. BHK medium, a replication-deficient HSV viral vector (HSV1716) with no insert or containing full-length GADD34, the N terminal or a conserved portion of the gene, was injected into mouse brain before stroke. Infarct size was 1.0±0.26, 1.19±0.36, 1.5±0.36, 1.3±0.36, and 1.1±0.28 mm3, respectively. The increase in infarct size with full-length GADD34 was statistically significant (P<0.05). Immunohistochemistry confirmed viral protein expression. Tissue culture studies revealed GADD34 gene restored virulence in HSV1716, suggesting that HSV virulence, rather than increased GADD34, exacerbated ischaemic damage.Journal of Cerebral Blood Flow & Metabolism (2008) 28, 747–751; doi:10.1038/sj.jcbfm.9600565; published online 10 October 2007 [ABSTRACT FROM AUTHOR]

Chinese hamster ovary (CHO) cells are traditionally regarded as nonpermissive cells for herpes simplex virus type 1 (HSV-1) infection as they lack the specific entry receptors, and modified CHO cells have been instrumental in the identification of HSV-1 receptors in numerous studies. In this report we demonstrate that the HSV-1 strain 17+ variant HSV1716 is able to infect unmodified CHO cells but only if the virus is propagated in baby hamster kidney (BHK) cells. Infection of CHO cells by BHK-propagated HSV1716 results in expression of immediate-early, early, and late viral genes, and infectious progeny virions are produced. In normally cultured CHO cells, up to a maximum of 50% of cells were permissive for BHK-propagated HSV1716 infection, with 24 h of serum starvation increasing this to 100% of CHO cells, suggesting that the mechanism used by BHK-propagated virus to infect CHO cells was cell cycle dependent. The altered tropism of HSV1716 was also evident in another nonpermissive mouse melanoma cell line and is an exclusive property resulting from propagation of the virus using BHK cells, as viruses propagated on Vero, C8161 (a human melanoma cell line), or indeed, CHO cells were completely unable to infect either CHO or mouse melanoma cells. [ABSTRACT FROM AUTHOR]

We have previously shown that avirulent but replication-competent herpes simplex virus (HSV) 1716 causes cell death in human melanoma cell lines in vitro and selectively replicates in melanoma tissue in nude mice. We now present a pilot study of intratumoral injection of HSV1716 into subcutaneous nodules of metastatic melanoma in five patients with stage 4 melanoma. Two patients each received one injection, two received two injections, and one received four injections of 10[sup 3] plaque-forming units HSV1716. In one patient, flattening of previously palpable tumour nodules was seen 21 days after two direct injections of HSV1716, and in injected nodules from all three patients who received two or more injections there was microscopic evidence of tumour necrosis. Immuno-histochemical staining of injected nodules revealed evidence of virus replication confined to tumour cells. These findings suggest that HSV1716 is non-toxic and could be of therapeutic benefit in patients with metastatic melanoma. [ABSTRACT FROM AUTHOR]

The replicative ability of ICP34.5-null herpes simplex virus (HSV) is cell type and state dependent. In certain cells, ICP34.5 interacts with protein phosphatase 1 to preclude host cell protein synthesis shutoff by dephosphorylation of the eukaryotic initiation factor eIF-2α. However, host cell shutoff is not induced by ICP34.5-null HSV in most cells, irrespective of type and state. In general, dividing cells support replication of ICP34.5-null HSV; nondividing cells cannot. Previously the authors showed that ICP34.5 binds to proliferating cell nuclear antigen (PCNA), a protein necessary for cellular DNA replication and repair. Here the authors demonstrate that (1) the interaction between ICP34.5 and PCNA involves two regions of the virus protein; (2) ICP34.5 forms a complex with HSV replication proteins that is DNA binding; (3) at early times in infection, ICP34.5 colocalizes with PCNA and HSV replication proteins in cell nuclei, before accumulating in the cytoplasm; and (4) ICP34.5 is a virion protein. In light of ongoing clinical trials assessing the safety and efficacy of ICP34.5-null HSV, it is vital that the roles of ICP34.5 in HSV replication are understood. The authors propose that in nondividing cells, ICP34.5 is required to switch PCNA from repair to replication mode, a prerequisite for the initiation of HSV replication. [ABSTRACT FROM AUTHOR]

Modified, non-neurovirulent herpes simplex viruses (HSV) have shown promise for the treatment of brain tumors, including intracranial melanoma. In this report, we show that HSV-1716, an HSV-1 mutant lacking both copies of the gene coding-infected cell protein 34.5 (ICP 34.5), can effectively treat experimental subcutaneous human melanoma in mice. In vitro, HSV-1716 replicated in all 26 human melanoma cell lines tested, efficiently lysing the cells. Therapeutic infection of subcutaneous human melanoma nodules with HSV-.171.6 led to viral replication that was restricted to tumor cells by immunohistochemistry. Moreover, HSV-1716 treatment significantly inhibited progression of preformed subcutaneous human melanoma nodules in SCID mice and caused complete regression of some tumors. This work expands the potential scope of HSV-1-based cancer therapy. [ABSTRACT FROM AUTHOR]