Table 1.
VZV protein functions in the pathogenesis of T cell, skin and DRG infection
| Protein | Characteristics | Cell culture* | Xenografts* |
|---|---|---|---|
| Glycoproteins | |||
| gB (ORF31) | Mature form generated by furin cleavage; ITIM motif in cytoplasmic domain; required for cell fusion together with gH–gL | Essential | Mutation of furin-cleavage site: impaired replication in skin |
| ITIM mutation; severely impaired replication and enhanced fusion in skin | |||
| gH (ORF37) | Ectodomain comprising domains I–III; forms heterodimer with gL; required for cell fusion together with gB and gL | Essential | Mutation of domain I amino terminus: impaired replication in skin |
| Mutation of domain III fusion loop; impaired replication in skin | |||
| gL (ORF60) | Forms heterodimer with gH | Presumed essential | Not tested |
| gE (ORF68) | Large unique N terminus (amino acids 1–187); forms heterodimer with gI (amino acids 208–236); binds to IDE; TGN-targeting and endocytosis motifs in cytoplasmic domain; MSP−gE is a natural variant | Essential; deletion of amino acids 1–187 blocks endocytosis | Deletion of amino acid residues 51–187: no replication in T cells and skin |
| Mutation of gI-binding domain: no effect in T cells, severely impaired replication in skin, prolonged replication and severe tissue damage in DRG | |||
| Mutation of IDE-binding domain: no effect in T cells, impaired replication in skin, no effect in DRG | |||
| Mutation of TGN-targeting motif: impaired replication in T cells and skin, no effect in DRG | |||
| MSP-gE: enhanced replication in skin | |||
| gI (ORF67) | Forms heterodimer with gE (via amino acids 105–125 and conserved cysteine residues); required for incorporation of gE into virions | Dispensable, decreased titres and plaque size | Deletion of gI: no replication in T cells and skin, prolonged replication in DRG |
| Mutation of gE-binding domain: prolonged replication in DRG | |||
| Deletion of amino acids 105–125: no replication in skin | |||
| Mutation of Sp1–USF-binding motif: no replication in T cells, impaired replication in skin, no effect in DRG | |||
| Mutation of ORF29-binding motif: impaired replication in T cells | |||
| Regulatory proteins | |||
| ORF9 | Tegument protein; binds to IE62 and ORF11; functions unknown | Essential | Not tested |
| ORF10 | Tegument protein; ORF62 and ORF71 transactivator; required for efficent virion assembly | Dispensable | Deletion of ORF10: no effect in T cells, impaired replication in skin |
| ORF11 | Tegument protein; required for normal levels of IE4, IE62, IE63 and gE; RNA-binding domain (amino acids 1–22); binding to ORF9 required for efficient virion assembly | Dispensable | Deletion of ORF11: impaired replication in skin |
| Mutation of RNA-binding motif: no effect in skin | |||
| Mutation of ORF9-binding motif: no replication in skin | |||
| ORF12 | Tegument protein; activates cell signalling pathways (such as ERK, p38, JNK and PI3K–AKT) that inhibit apoptosis and support viral replication | Dispensable | Deletion of ORF12: no effect in skin |
| ORF47 | Serine/threonine kinase (conserved); phosphorylates regulatory proteins and glycoproteins; binds to IE62; required for virion assembly | Dispensable | Deletion of ORF47: no replication in T cells and skin |
| Mutation of kinase motif: no replication in T cells, impaired replication in skin | |||
| ORF61 | Transactivator or repressor; dimerization required for regulatory functions; E3 ligase; PML dispersal by SIMs | Essential‡ | Deletion of SIMs: impaired replication in skin |
| Deletion of dimerization domain (amino acids 250–320): impaired replication in skin | |||
| ORF62 and ORF71 | IE62 is major viral transactivator; IFN inhibition | Essential | Deletion of ORF62 and ORF71 with ectopic ORF62: no replication in skin |
| ORF63 and RF70 | IE63 phosphoprotein; represses IE62; transactivates EF−1α | Essential‡ | Deletion of ORF63 and ORF70 with ectopic ORF63: no effect in T cells and skin |
| Mutation of phosphorylation sites: no effect in T cells, impaired replication in skin | |||
| ORF66 | Serine/threonine kinase (alphaherpesviruses); phosphorylates IE62; inhibits apoptosis | Dispensable | Deletion of ORF66: impaired replication in T cells, slightly impaired replication in skin |
| Mutation of kinase motif: impaired replication in T cells, slightly impaired replication in skin | |||
| Other VZV proteins | |||
| ORF23 | Small capsid surface protein; required for nuclear transport of other capsid proteins and capsid assembly | Dispensable | Deletion of ORF23: no replication in skin |
| ORF35 | Cell fusion | Dispensable, decreased cell fusion | Deletion of ORF35: slightly impaired replication in T cells, impaired replication in skin |
| ORF64 and ORF69 | Cell fusion | Dispensable, increased cell fusion | Deletion of ORF64 and ORF69: no effect in T cells and skin |
| ORF65 | Virion protein | Dispensable | Deletion of ORF65: no effect in T cells and skin |
DRG, dorsal root ganglia; EF-1α, elongation factor 1α; ERK, extracellular signal-regulated kinase; IDE, insulin-degrading enzyme; IE, immediate-early; IFN, interferon; ITIM, immunoreceptor tyrosine-based inhibition; JNK, c-JUN N-terminal kinase; PML, promyelocytic leukaemia protein; SIMs, SUMO-binding motifs; TGN, trans-Golgi network; VZV, varicella zoster virus.
*
Function in cells and tissues was assessed by mutagenesis of the VZV genome using cosmids or bacterial artificial chromosomes (BACs) to delete or insert stop codons or introduce targeted changes in the coding sequence
‡
Indicates differences among published observations about whether the gene is essential or dispensable, including variations in the mutations tested and/or experimental conditions used to assess growth requirement.