vIRF encoded by ORF-K9 is the first KSHV oncogene identified by us. We have demonstrated that vIRF down-regulates cyclin-dependent protein kinase inhibitor (CDKI) p21WAF1/CIP1, MHC class I antigen, and causes cellular transformation through the inhibition of anti-viral interferon signal pathways. Recently, we have demonstrated vIRF protein expression in Kaposi's sarcoma tumors, identified the core promoter, define a TPA-responsive region, and mapped a novel transcriptional silencer in the upstream regulatory sequences of vIRF gene. The transcriptional silencer interacts with two previously unknown transcriptional repressors, which we are attempting to identify. These studies have not only provided insight into the mechanism controlling vIRF expression, but also shed light on the general mechanism controlling the expression of viral lytic cycle genes during KSHV latent infection.
More recently, we have found that vIRF auto-activates its own promoter through two interferon-unresponsive cis-elements (Vac1 and Vac2), suggesting that vIRF might target cellular signaling pathways that are unrelated to interferon signaling.
We have also developed several vIRF-specific ribozymes, which can be used to functionally knock out vIRF gene. These reagents are valuable for functional characterizations of vIRF. Since vIRF is likely to have pivotal role in KSHV-related pathogenesis, the ribozymes could potentially have therapeutic application for KSHV-related malignancies. We are using KSHV mutant with vIRF gene deleted to examine the function of vIRF in KSHV infection and replication.