Highly selective escape from KSHV-mediated host mRNA shutoff and its implications for viral pathogenesis.
During Kaposi's sarcoma (KS)-associated herpesvirus (KSHV) lytic infection, many virus-encoded signaling molecules (e.g., viral G protein-coupled receptor [vGPCR]) are produced that can induce host gene expression in transiently transfected cells, and roles for such induced host genes have been posited in KS pathogenesis. However, we have recently found that host gene expression is strongly inhibited by 10-12 h after lytic reactivation of KSHV, raising the question of whether and to what extent de novo host gene expression induced by viral signaling molecules can proceed during the lytic cycle. Here, we show by microarray analysis that expression of most vGPCR target genes is drastically curtailed by this host shutoff. However, rare cellular genes can escape the host shutoff and are potently up-regulated during lytic KSHV growth. Prominent among these is human interleukin-6, whose striking induction may contribute to the overexpression of this cytokine in several disease states linked to KSHV infection.
Howard Hughes Medical Institute, Department of Microbiology, University of California, San Francisco, 513 Parnassus Ave., Box 0414, San Francisco, CA 94143, USA.
Britt
B
Glaunsinger
Don
D
Ganem
D004268:DNA-Binding Proteins / Q000502:physiology; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D019288:Herpesvirus 8, Human / Q000472:pathogenicity*; D006801:Humans; D051793:Hypoxia-Inducible Factor 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D015850:Interleukin-6 / Q000235:genetics; D009687:Nuclear Proteins / Q000502:physiology; D020411:Oligonucleotide Array Sequence Analysis; D012333:RNA, Messenger / Q000378:metabolism*; D019707:Receptors, Chemokine / Q000502:physiology*; D014157:Transcription Factors
D004268:DNA-Binding Proteins; C115448:G protein-coupled receptor, Human herpesvirus 8; C497442:HIF1A protein, human; D051793:Hypoxia-Inducible Factor 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D015850:Interleukin-6; D009687:Nuclear Proteins; D012333:RNA, Messenger; D019707:Receptors, Chemokine; D014157:Transcription Factors