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Enhanced antitumor efficacy of a herpes simplex virus mutant isolated by genetic selection in cancer cells.

ABSTRACT: Replication-competent, attenuated herpes simplex virus-1 (HSV-1) derivatives that contain engineered mutations into the viral gamma 34.5 virulence gene have been used as oncolytic agents. However, as attenuated mutants often grow poorly, they may not completely destroy some tumors and surviving cancer cells simply regrow. Thus, although HSV-1 gamma 34.5 mutants can reduce the growth of human tumor xenografts in mice and have passed phase I safety studies, their efficacy is limited because they replicate poorly in many human tumor cells. Previously, we selected for a gamma 34.5 deletion mutant variant that regained the ability to replicate efficiently in tumor cells. Although this virus contains an extragenic suppressor mutation that confers enhanced growth in tumor cells, it remains attenuated. Here, we demonstrate that the suppressor virus replicates to greater levels in prostate carcinoma cells and, importantly, is a more potent inhibitor of tumor growth in an animal model of human prostate cancer than the gamma 34.5 parent virus. Thus, genetic selection in cancer cells can be used as a tool to enhance the antitumor activity of a replication-competent virus. The increased therapeutic potency of this oncolytic virus may be useful in the treatment of a wide variety of cancers.

SUBMITTER: Taneja S

PROVIDER: S-EPMC37516 | biostudies-literature | 2001 Jul

REPOSITORIES: biostudies-literature

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Enhanced antitumor efficacy of a herpes simplex virus mutant isolated by genetic selection in cancer cells.

Taneja S S MacGregor J J Markus S S Ha S S Mohr I I

Proceedings of the National Academy of Sciences of the United States of America 20010703 15

Replication-competent, attenuated herpes simplex virus-1 (HSV-1) derivatives that contain engineered mutations into the viral gamma 34.5 virulence gene have been used as oncolytic agents. However, as attenuated mutants often grow poorly, they may not completely destroy some tumors and surviving cancer cells simply regrow. Thus, although HSV-1 gamma 34.5 mutants can reduce the growth of human tumor xenografts in mice and have passed phase I safety studies, their efficacy is limited because they r ...[more]

PMID: 11438715

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Project description:Glycoprotein B (gB) is a conserved viral fusion protein that is required for herpesvirus entry. To mediate fusion with the cellular membrane, gB refolds from a prefusion to a postfusion conformation. We hypothesize that an interaction between the C-terminal arm and the central coiled coil of the herpes simplex virus 1 (HSV-1) gB ectodomain is critical for fusion. We previously reported that three mutations in the C-terminal arm (I671A/H681A/F683A, called gB3A) greatly reduced cell-cell fusion and that virus carrying these mutations had a small-plaque phenotype and delayed entry into cells. By serially passaging gB3A virus, we selected three revertant viruses with larger plaques. These revertant viruses acquired mutations in gB that restore the fusion function of gB3A, including gB-A683V, gB-S383F/G645R/V705I/A855V, and gB-T509M/N709H. V705I and N709H are novel mutations that map to the portion of domain V that enters domain I in the postfusion structure. S383F, G645R, and T509M are novel mutations that map to an intersection of three domains in a prefusion model of gB. We introduced these second-site mutations individually and in combination into wild-type gB and gB3A to examine the impact of the mutations on fusion and expression. V705I and A855V (a known hyperfusogenic mutation) restored the fusion function of gB3A, whereas S383F and G645R dampened fusion and T509M and N709H worked in concert to restore gB3A fusion. The results identify two regions in the gB ectodomain that modulate the fusion activity of gB, potentially by impacting intramolecular interactions and stability of the prefusion and/or postfusion gB trimer.IMPORTANCE Glycoprotein B (gB) is an essential viral protein that is conserved in all herpesviruses and is required for virus entry. gB is thought to undergo a conformational change that provides the energy to fuse the viral and cellular membranes; however, the details of this conformational change and the structure of the prefusion and intermediate conformations of gB are not known. Previously, we demonstrated that mutations in the gB "arm" region inhibit fusion and impart a small-plaque phenotype. Using serial passage of a virus carrying these mutations, we identified revertants with restored plaque size. The revertant viruses acquired novel mutations in gB that restored fusion function and mapped to two sites in the gB ectodomain. This work supports our hypothesis that an interaction between the gB arm and the core of gB is critical for gB refolding and provides details about the function of gB in herpesvirus-mediated fusion and subsequent virus entry.

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Enhanced antitumor efficacy of a herpes simplex virus mutant isolated by genetic selection in cancer cells.

Publications

Enhanced antitumor efficacy of a herpes simplex virus mutant isolated by genetic selection in cancer cells.

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