Absence or overexpression of the Varicella-Zoster Virus (VZV) ORF29 latency-associated protein impairs late gene expression and reduces VZV latency in a rodent model.
Varicella-zoster virus (VZV) ORF29 encodes the viral single-stranded DNA binding protein and is expressed during latency in human ganglia. We constructed an ORF29 deletion mutant virus and showed that the virus could replicate only in cells expressing ORF29. An ORF29-repaired virus, in which ORF29 was driven by a cytomegalovirus promoter, grew to peak titers similar to those seen with the parental virus. The level of ORF29 protein in cells infected with the repaired virus was greater than that seen with parental virus. Infection of cells with either the ORF29 deletion or repaired virus resulted in similar levels of VZV immediate-early proteins but reduced levels of glycoprotein E compared to those observed with parental virus. Cotton rats infected with the ORF29 deletion mutant had a markedly reduced frequency of latent infection in dorsal root ganglia compared with those infected with parental virus (P < 0.00001). In contrast, infection of animals with the ORF29 deletion mutant resulted in a frequency of ganglionic infection at 3 days similar to that seen with the parental virus. Animals infected with the ORF29-repaired virus, which overexpresses ORF29, also had a reduced frequency of latent infection compared with those infected with parental virus (P = 0.0044). These studies indicate that regulation of ORF29 at appropriate levels is critical for VZV latency in a rodent model.
Cohen
Jeffrey I
JI
Laboratory of Clinical Infectious Diseases, Bldg. 10, Room 11N234, National Institutes of Health, 10 Center Drive, Bethesda, MD 20892, USA. jcohen@niaid.nih.gov
Krogmann
Tammy
T
Pesnicak
Lesley
L
Ali
Mir A
MA
D000818:Animals; D004268:DNA-Binding Proteins / Q000502:physiology*; D015536:Down-Regulation; D020804:Encephalitis, Varicella Zoster / Q000821:virology*; D005260:Female; D015967:Gene Expression Regulation, Viral / Q000502:physiology*; D014645:Herpesvirus 3, Human / Q000472:pathogenicity*; D016366:Open Reading Frames / Q000502:physiology*; D016205:Sigmodontinae; D014764:Viral Proteins / Q000502:physiology*; D017735:Virus Latency
D004268:DNA-Binding Proteins; D014764:Viral Proteins