Downregulation of class I major histocompatibility complex surface expression by varicella-zoster virus involves open reading frame 66 protein kinase-dependent and -independent mechanisms.
We show here that the varicella-zoster virus (VZV) open reading frame 66 (ORF66) protein kinase is one mechanism employed to reduce class I major histocompatibility complex (MHC-I) surface expression in VZV-infected cells. Cells expressing enhanced green fluorescent protein-tagged functional and inactivated ORF66 (GFP-66 and GFP-66kd) from replication-defective adenovirus vectors revealed that ORF66 reduced MHC-I surface levels in a manner dependent on kinase activity. Cells infected with recombinant VZV expressing GFP-66 exhibited a significantly greater reduction in MHC-I surface expression than that observed in cells infected with VZV disrupted in GFP-66 expression. MHC-I maturation was delayed in its transport from the endoplasmic reticulum through the Golgi in both adenovirus-transduced cells expressing only GFP-66 and in VZV-infected cells expressing high levels of GFP-66, and this was predominantly kinase dependent. MHC-I levels were reduced in VZV-infected cells, and analyses of intracellular MHC-I revealed accumulation of folded MHC-I in the Golgi region, irrespective of ORF66 expression. Thus, the ORF66 kinase is important for VZV-mediated MHC-I downregulation, but additional mechanisms also may be involved. Analyses of the VZV ORF9a protein, the ortholog of the bovine herpesvirus 1 transporter associated with antigen processing inhibitor UL49.5 revealed no effects on MHC-I. These results establish a new role for viral protein kinases in immune evasion and suggest that VZV utilizes unique mechanisms to inhibit antigen presentation.
Eisfeld
Amie J
AJ
Department of Ophthalmology, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania 15213, USA.
Yee
Michael B
MB
Erazo
Angela
A
Abendroth
Allison
A
Kinchington
Paul R
PR
D002460:Cell Line; D015536:Down-Regulation; D006056:Golgi Apparatus / Q000737:chemistry; D014645:Herpesvirus 3, Human / Q000276:immunology*; D015395:Histocompatibility Antigens Class I / Q000096:biosynthesis*; D006801:Humans; D011494:Protein Kinases / Q000235:genetics / Q000502:physiology*; D011499:Protein Processing, Post-Translational; D014764:Viral Proteins / Q000235:genetics / Q000502:physiology*
D015395:Histocompatibility Antigens Class I; D014764:Viral Proteins; D011494:Protein Kinases