Human Herpesvirus 8 Encodes an Interferon Regulatory Factor (IRF) Homolog That Represses IRF-1-Mediated Transcription

Abstract

Human herpesvirus 8 (HHV-8) is the probable viral etiologic agent for Kaposi’s sarcoma. The HHV-8 genome encodes viral interferon regulatory factor (vIRF), a gene product that has homology to the IRF family of transcription factors. We demonstrate that vIRF inhibits responses to type I and type II interferons and blocks IRF-1-mediated transcription. vIRF does not compete with IRF-1 for binding to DNA or complex directly with IRF-1. The ability of vIRF to block IRF-1-mediated transcription is independent of the DNA binding domains of both vIRF and IRF-1. These data suggest that vIRF may contribute to viral pathogenesis and cellular transformation by interfering with interferon- and IRF-1-mediated gene expression through a novel mechanism.

The interferon response circuit: Induction and suppression by pathogenic viruses

“…A different strategy to block cellular IRF-3 is used by certain herpesviruses. Human herpes virus 8 (HHV-8), the causative agent of Kaposi sarcoma, displays viral IRF homologues, termed vIRFs, which either mimic their cellular counterparts or exert a dominant-negative effect (Burysek et al, 1999a(Burysek et al, , 1999bLi et al, 1998;Lubyova et al, 2004;Lubyova and Pitha, 2000;Zimring et al, 1998). Finally, a far-reaching approach is used by the large poxviruses.…”

“…Viral inhibitors of the virus-induced IFN-a/h response loop: Viral gene products interfere with the type I IFN system at all levels. The following viral IFN antagonists are shown in clockwise order: NS1 of FLUAV (Garcia-Sastre, 2001;Garcia-Sastre et al, 1998;Talon et al, 2000a;Wang et al, 2000), NS1 of FLUBV (Dauber et al, 2004), E3L VV (Smith et al, 2001;Xiang et al, 2002), V of paramyxoviruses , NS3/4A of HCV (Breiman et al, 2005;, VP35 of EBOV , P of RV , P of BDV (Unterstab et al, in press), V, W of Nipah virus (Park et al, 2003;Shaw et al, 2004), NS1/NS2 of RSV (Bossert et al, 2003;Spann et al, 2004;Valarcher et al, 2003), leader protein of TMEV (Delhaye et al, 2004;van Pesch et al, 2001), ML of THOV (Hagmaier, 2003 #89;Jennings, 2004 #233;Pichlmair, 2004 #247), NPro of CSFV (La Rocca et al, 2005;Ruggli et al, 2003Ruggli et al, , 2005, vIRF and ORF45 of HHV-8 (Burysek et al, 1999a(Burysek et al, , 1999bLi et al, 1998;Lubyova et al, 2004;Lubyova and Pitha, 2000;Zhu et al, 2002;Zimring et al, 1998), E6 of HPV16 , BZLF-1 of EBV (Hahn et al, 2005), M of VSV (Ahmed et al, 2003;Yuan et al, 1998), 3C Pro of PV (Clark et al, 1993;Yalamanchili et al, 1996), NSs of BUNV (Thomas et al, 2004;Weber et al, 2002), NSs of RVFV, Bouloy et al, 2001;Le May et al, 2004), B18 and B8 of VV…”

Inhibition of replication and transcription activator and latency-associated nuclear antigen of Kaposi's sarcoma-associated herpesvirus by morpholino oligomers

“…Cidofovir and foscarnet have no effect on expression of latent or early lytic genes (Curreli et al, 2002), as these drugs are inhibitors of the viral DNA polymerase, and transcription of early lytic genes occurs before DNA replication in KSHV. LANA, RTA, and early lytic genes such as vIL-6 Jones et al, 1999;Staskus et al, 1999) and vIRF-1 Zimring et al, 1998) play important roles in KSHV replication and pathogenesis. Blocking expression of these genes, and thereby that of down-stream genes as well, could contribute to the treatment of KSHV-associated malignancies.…”

Viral Anticytokine Strategies

“…Type II human parainfluenza virus V protein targets STAT2, mumps virus V protein targets both STAT1 and STAT3, and measles virus V protein causes a defect in STAT nuclear accumulation and STAT-inducible transcription (Parisien et al, 2001;Nishio et al, 2002;Palosaari et al, 2003;Ulane et al, 2003). KSHV uses a different mechanism by encoding a homologue of IRF that represses the IFN-mediated transcriptional activation of host genes (Zimring et al, 1998).…”