R. Renne et al., Modulation of cellular and viral gene expression by the latency-associatednuclear antigen of kaposi's sarcoma-associated herpesvirus, J VIROLOGY, 75(1), 2001, pp. 458-468
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.