ABSTRACT
The DNA sequence TAAT is the core binding motif for the mouse homeodomain protein Hox 1.3 (proposed new name, Hoxa-5). These sequences are present within the multiple TAATGARAT regulatory motifs in the promoters of the immediate-early genes which control herpes simplex virus type 1 replication. To investigate the role of this homeodomain protein in the regulation of herpes simplex virus gene expression and pathogenesis, transgenic mice containing a mouse Hox 1.3 cDNA under the control of the virus- and interferon-inducible Mx 1 promoter were generated. After infection of transgenic mice with herpes simplex virus, Hox 1.3 RNA and protein were expressed at the sites of virus replication. In these transgenic mice, herpes simplex virus replication, spread of virus through the host, and virus-induced mortality were markedly enhanced. Increased spread and replication of herpes simplex virus were also observed in cultured fibroblasts from transgenic mice. This finding suggests that in vivo, Hox 1.3 may increase viral spread by increasing viral replication at the level of the individual infected cells. These results demonstrate that expression of a transgene encoding a single host protein, Hox 1.3, alters the pathogenesis of experimental herpes simplex virus infection. We conclude that a protein that belongs to a class of DNA-binding proteins which are best known for their role in regulating embryonic development may also regulate herpesvirus pathogenesis.
Subject(s)
Brain/microbiology , DNA-Binding Proteins/genetics , Herpes Simplex/genetics , Homeodomain Proteins , Mice, Transgenic/microbiology , Phosphoproteins/genetics , Regulatory Sequences, Nucleic Acid , Simplexvirus/genetics , Simplexvirus/pathogenicity , Animals , Base Sequence , Crosses, Genetic , DNA-Binding Proteins/biosynthesis , DNA-Binding Proteins/metabolism , Female , Gene Expression , Globins/biosynthesis , Globins/genetics , Herpes Simplex/etiology , Herpes Simplex/pathology , In Situ Hybridization , Male , Mice , Mice, Inbred C3H , Mice, Inbred C57BL , Molecular Sequence Data , Oligodeoxyribonucleotides , Phosphoproteins/biosynthesis , Phosphoproteins/metabolism , Promoter Regions, Genetic , Simplexvirus/physiology , Transcription Factors , Virus Replication/geneticsABSTRACT
Oct-3 is a POU domain transcription factor that binds the octamer DNA motif and is present in mouse oocytes before and after fertilization. When fertilized oocytes were injected with antisense Oct-3 oligonucleotides or double-stranded DNA containing the octamer motif, embryonic DNA synthesis was inhibited and the embryos were arrested at the one-cell stage. In vitro synthesized Oct-3 mRNA rescued the developmental block induced by antisense Oct-3 oligonucleotide. We conclude that maternally inherited Oct-3 is required for DNA replication and division of the one-cell embryo.
