Regulation of herpes simplex virus gamma(1)34.5 expression and oncolysis of diffuse liver metastases by Myb34.5

J Clin Invest. 2002 Apr;109(7):871-82. doi: 10.1172/JCI10623.


Myb34.5 is a herpes simplex virus 1 (HSV-1) mutant deleted in the gene for ribonucleotide reductase (ICP6). It also carries a version of gamma(1)34.5 (a viral gene product that promotes the dephosphorylation of eIF-2alpha) that is under control of the E2F-responsive cellular B-myb promoter, rather than of its endogenous promoter. Myb34.5 replication in tumor cells results in their destruction (oncolysis). gamma(1)34.5 expression by HSV-1 subverts an important cell defense mechanism against viral replication by preventing shutoff of protein synthesis after viral infection. Infection of colon carcinoma cells with Myb34.5 results in greater eIF-2alpha dephosphorylation and viral replication compared with infection with HSV-1 mutants completely defective in gamma(1)34.5 expression. In contrast, infection of normal hepatocytes with Myb34.5 results in low levels of eIF-2alpha dephosphorylation and viral replication that are similar to those observed with HSV-1 mutants completely defective in gamma(1)34.5 and ICP6. When administered intravascularly into mice with diffuse liver metastases, Myb34.5 has greater antineoplastic activity than HSV-1 mutants with completely defective gamma(1)34.5 expression and more restricted biodistribution compared with HSV-1 mutants with wild-type gamma(1)34.5 expression. Myb34.5 displays reduced virulence and toxicity compared to HSV-1 mutants with wild-type gamma(1)34.5 expression. Portal venous administration of Myb34.5 significantly reduces liver tumor burden in and prolongs the life of mice with diffuse liver metastases. Preexisting Ab's to HSV-1 do not reduce the antitumor efficacy of Myb34.5 in vivo.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Chlorocebus aethiops
  • Colonic Neoplasms / immunology
  • Colonic Neoplasms / metabolism*
  • Colonic Neoplasms / pathology
  • Cytopathogenic Effect, Viral
  • Eukaryotic Initiation Factor-2 / metabolism
  • Gene Expression Regulation*
  • HT29 Cells
  • Herpesvirus 1, Human / metabolism*
  • Humans
  • Liver Neoplasms, Experimental / immunology
  • Liver Neoplasms, Experimental / metabolism*
  • Liver Neoplasms, Experimental / secondary
  • Mice
  • Mice, Inbred BALB C
  • Phosphoprotein Phosphatases / metabolism
  • Ribonucleotide Reductases / genetics
  • Ribonucleotide Reductases / metabolism*
  • Vero Cells
  • Viral Proteins / genetics
  • Viral Proteins / metabolism*
  • Virus Replication


  • Eukaryotic Initiation Factor-2
  • Viral Proteins
  • gamma 34.5 protein, Human herpesvirus 1
  • herpes simplex virus type 1-protein ICP6
  • Ribonucleotide Reductases
  • Phosphoprotein Phosphatases