title: Herpes simplex virus 1 VP22 regulates translocation of multiple viral and cellular proteins and promotes neurovirulence.
abstract: Herpes simplex virus 1 (HSV-1) protein VP22, encoded by the UL49 gene, is a major virion tegument protein. In the present study, we showed that VP22 was required for efficient redistribution of viral proteins VP16, VP26, ICP0, ICP4, and ICP27 and of cellular protein Hsc-70 to the cytoplasm of infected cells. We found that two dileucine motifs in VP22, at amino acids 235 and 236 and amino acids 251 and 252, were necessary for VP22 regulation of the proper cytoplasmic localization of these viral and cellular proteins. The dileucine motifs were also required for proper cytoplasmic localization of VP22 itself and for optimal expression of viral proteins VP16, VP22, ICP0, UL41, and glycoprotein B. Interestingly, a recombinant mutant virus with alanines substituted for the dileucines at amino acids 251 and 252 had a 50% lethal dose (LD(50)) for neurovirulence in mice following intracerebral inoculation about 10(3)-fold lower than the LD(50) of the repaired virus. Furthermore, the replication and spread of this mutant virus in the brains of mice following intracerebral inoculation were significantly impaired relative to those of the repaired virus. The ability of VP22 to regulate the localization and expression of various viral and cellular proteins, as shown in this study, was correlated with an increase in viral replication and neurovirulence in the experimental murine model. Thus, HSV-1 VP22 is a significant neurovirulence factor in vivo.
authors.affiliation: Department of Pathology, National Institute of Infectious Diseases, Shinjuku-ku, Japan.
authors.forename: Michiko
authors.initials: M
authors.lastname: Tanaka
authors.forename: Akihisa
authors.initials: A
authors.lastname: Kato
authors.forename: Yuko
authors.initials: Y
authors.lastname: Satoh
authors.forename: Takahiro
authors.initials: T
authors.lastname: Ide
authors.forename: Ken
authors.initials: K
authors.lastname: Sagou
authors.forename: Kayo
authors.initials: K
authors.lastname: Kimura
authors.forename: Hideki
authors.initials: H
authors.lastname: Hasegawa
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Kawaguchi
mesh_terms: D020816:Amino Acid Motifs; D019943:Amino Acid Substitution; D000818:Animals; D001921:Brain / Q000473:pathology / Q000821:virology; D002460:Cell Line; D002522:Chlorocebus aethiops; D005260:Female; D023061:Gene Order; D016679:Genome, Viral; D017405:Herpes Simplex Virus Protein Vmw65 / Q000235:genetics / Q000378:metabolism; D018259:Herpesvirus 1, Human / Q000235:genetics / Q000378:metabolism* / Q000472:pathogenicity*; D007930:Leucine / Q000737:chemistry; D051379:Mice; D008813:Mice, Inbred ICR; D009154:Mutation; D021381:Protein Transport; D011506:Proteins / Q000235:genetics / Q000378:metabolism*; D011817:Rabbits; D014764:Viral Proteins / Q000235:genetics / Q000378:metabolism; D015678:Viral Structural Proteins / Q000235:genetics / Q000378:metabolism*; D014774:Virulence; D014779:Virus Replication / Q000235:genetics
chemical_list: D017405:Herpes Simplex Virus Protein Vmw65; D011506:Proteins; D014764:Viral Proteins; D015678:Viral Structural Proteins; C073413:herpes simplex virus type 1 protein VP22; D007930:Leucine