Oncolytic viruses derived from the gamma34.5-deleted herpes simplex virus recombinant R3616 encode a truncated UL3 protein.
Replication-competent herpes simplex virus (HSV-1) mutants are used in clinical trials in the experimental treatment of cancer. Mutants G207, HSV1716, NV1020, and Oncovex GM-CSF share in common a defect in one or both copies of the gene encoding the neurovirulence factor, ICP34.5, and are thus neuroattenuated. These viruses are acknowledged to differ from one another (a) in the specific types of mutations intentionally introduced during their derivation and (b) in the inherent genetic differences retained from the different parent strains used in their construction. Unintended mutations are expected to emerge at some low frequency during the selection for and passage of mutant viruses. Here we demonstrate that during the construction of the oncolytic virus R3616, a nonsense mutation arose in an untargeted region of the HSV-1 genome that resulted in a substantial truncation of the viral protein known as UL3. This report is the first published documentation that oncolytic herpesviruses developed and used in clinical trials contain adventitious mutations. The implications of these findings for the characterization and development of vectors proposed for use in clinical trials are discussed.
Division of Cellular and Gene Therapies, Center for Biologics Evaluation and Research, Food and Drug Administration, Bethesda, MD 20892, USA.
Megan J
MJ
Dambach
Jordan
J
Trecki
Natalia
N
Martin
Nancy S
NS
Markovitz
D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D002522:Chlorocebus aethiops; D018389:Codon, Nonsense; D016384:Consensus Sequence; D004274:DNA, Recombinant / Q000235:genetics / Q000378:metabolism; D004279:DNA, Viral / Q000235:genetics / Q000378:metabolism; D017353:Gene Deletion; D015967:Gene Expression Regulation, Viral; D005814:Genes, Viral; D018259:Herpesvirus 1, Human / Q000235:genetics*; D006801:Humans; D015603:Keratinocytes / Q000821:virology; D008969:Molecular Sequence Data; D050504:Oncolytic Viruses / Q000235:genetics*; D011817:Rabbits; D017422:Sequence Analysis, DNA; D017386:Sequence Homology, Amino Acid; D014709:Vero Cells; D014764:Viral Proteins / Q000737:chemistry / Q000235:genetics* / Q000502:physiology
D018389:Codon, Nonsense; D004274:DNA, Recombinant; D004279:DNA, Viral; C121640:UL3 protein, Human herpesvirus 1; D014764:Viral Proteins; C066469:gamma 34.5 protein, Human herpesvirus 1