Analysis of the sequenced genomes and by specialized protein expression systems has provided insights into protein functions. As is typical of herpesviruses, proteins
Table 1 Human herpesvirus-6 and herpesvirus-7 genes and gene products
U86-89 IE-A gene block.
U89 encodes IE1 U95 IE protein (IE2)
U16-19 IE-B gene block
DNA synthesis and viral replication U27 Polymerase processivity factor U38 DNA polymerase
U41 Major DNA-
binding protein U43/74/77 Helicase/primase complex
U73 Origin-binding protein
Nucleic acid metabolism
U28 R1 subunit of ribonucleotide reductase U45 dUTPase
U81 Uracil-DNA glycosylase
U11 Tegument protein
U14 Tegument protein
U100 Heparin-binding glycoprotein
U83 Viral chemokine, vCCL4
U12 Chemokine receptor
U51 Chemokine receptor
DR7 p53-binding protein are transcribed as immediate-early (IE, synthesized within minutes of infection and independently of de novo protein synthesis), early, or late proteins. Table 1 summarizes some of the principle genes and the proteins encoded.
The genes encoding IE genes show variability between HHV-6 and HHV-7. The transcriptional regulation is incompletely characterized, but NF-kB and AP-1 binding sites have been identified. IE1 is a nuclear phosphoprotein that transactivates heterologous promoters and plays a role in latency-associated gene transcription. IE2 is more highly conserved between HHV-6 strains and HHV-7. The U16 gene product of HHV-6 and the p53 binding protein encoded by DR7 transactivate the HIV-1 long terminal repeat. The DR7 gene product has transforming activity.
Proteins involved in replication are highly conserved. The DNA polymerase binds a 40-41 kDa protein (DNA polymerase processivity factor) that localizes to the nucleus. Viral replication in vitro is enhanced by the presence of multiple copies of the origin of lytic replication that bind the origin of replication binding protein (OBP). U94 encodes a homolog of the human adeno-associated virus 2 (AAV-2) rep gene and is absent in HHV-7. It binds the human TATA-binding protein, a transcription factor and aids maintenance of latency by down-regulating gene transcription. It also inhibits cell transformation and transactivation of HIV-1 LTR.
Structural proteins include two heparin-binding glycoproteins, gB and the U100 product, that contain subtype-specific epitopes. U100 products include gp105 of HHV-6 (gp82-105) and gp65 of HHV-7 and are unique to HHV-6 and HHV-7. U100 can be differentially spliced and shows marked variation between HHV-6A and HHV-6B with possible biological implications. A U100-transcribed protein in HHV-6 has been identified as gQ, an 80 kDa protein, that complexes with gH and gL. gL plays a role in the transport and processing of gH. gH and gL form heterologous complexes both with each other and gH/gL of other p-herpesvirus that might facilitate viral interactions. gB, gH, and U100 products are targets for neutralizing antibodies. gM is a highly conserved glycoprotein. The glycoprotein encoded by U22 is not present in HHV-7. pp85 of HHV-7 is an immunodominant tegument phosphoprotein that forms a protein complex that is enriched in dense bodies. Other immunodominant tegument proteins include the p100 phosphoprotein of HHV-6 and p89 of HHV-7 that contain type-specific epitopes. A viral encoded protease contributes to viral maturation. HHV-6 and HHV-7 encode two G-protein-coupled receptors that are p-chemokine receptors. Signaling via the U51-encoded receptor can result in down-regulation of the chemokine RANTES. HHV-6A and HHV-6B (but not HHV-7) encode a functional chemokine that contributes to viral immunomodulation. U83 is subject to differential splicing.
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