Modulation of cellular and viral gene expression by the latency-associatednuclear antigen of kaposi's sarcoma-associated herpesvirus

Kaposi's sarcoma-associated herpesvirus (KSHV), also called human herpesvir us 8 (HHV-8), is the likely etiological agent of Kaposi's sarcoma and prima ry effusion lymphoma. Common to these malignancies is that tumor cells are latently infected with KSHV. Viral gene expression is limited to a few gene s, one of which is the latency-associated nuclear antigen (LANA), the produ ct of ORF73. Examination of the primary sequence of LANA reveals some struc tural features reminiscent of transcription factors, leading us to hypothes ize that LANA may regulate viral and cellular transcription during latency. In reporter gene-based transient transfection assays, we found that LANA c an have either positive or negative effects on gene expression. While expre ssion of a reporter gene from several synthetic promoters was increased in the presence of LANA, expression from the human immunodeficiency virus (HIV ) long terminal repeat (LTR)-and from NF-kappaB dependent reporter genes-wa s reduced by LANA expression. In addition, the promoter of KSHV ORF73 itsel f is activated up to 5.5-fold by LANA. This autoregulation may be important in tumorigenesis, because two other genes (v-cyclin and V-FLIP) with likel y roles in cell growth and survival are also controlled by this element. To identify cellular genes influenced by LANA, we employed cDNA array-based e xpression profiling, Six known genes (and nine expressed sequence tags) wer e found to be upregulated in LANA-expressing cell lines. One of these, Staf -50, is known to inhibit expression from the HIV LTR; most of the other kno wn genes are interferon inducible, although the interferon genes themselves were not induced by LANA. These data demonstrate that LANA expression has effects on cellular and viral gene expression. We suggest that, whether dir ect or indirect in origin, these effects may play important roles in the pa thobiology of KSHV infection.