Lytic infection by the Epstein-Barr virus (EBV) poses numerous health risks, such as infectious mononucleosis and lymphoproliferative disorder. Proteins in the bromodomain and extraterminal (BET) family regulate multiple stages of viral life cycles and provide promising intervention targets. Synthetic small molecules can bind to the bromodomains and disrupt function by preventing recognition of acetylated lysine substrates. We demonstrate that JQ1 and other BET inhibitors block two different steps in the sequential cascade of the EBV lytic cycle. BET inhibitors prevent expression of the viral immediate-early protein BZLF1. JQ1 alters transcription of genes controlled by the host protein BACH1, and BACH1 knockdown reduces BZLF1 expression. BET proteins also localize to the lytic origin of replication (OriLyt) genetic elements, and BET inhibitors prevent viral late gene expression. There JQ1 reduces BRD4 recruitment during reactivation to preclude replication initiation. This represents a rarely observed dual mode of action for drugs.
Small molecule inhibitors of bromodomain and extra-terminal (BET) proteins are seeing increased investigation in clinical trials for treatment of hematological malignancies. These compounds also repress oncogene expression driven by the human Epstein-Barr virus (EBV) in cell culture. We therefore tested the efficacy of the prototypical BET inhibitor JQ1 against a mouse xenograft model of post-transplantation lymphoproliferative disorder. JQ1 potently inhibits growth of lymphoblastoid cell lines (LCLs) in culture at low nM concentrations. Growth of other cell lines with similar EBV type III latency transcription programs is comparably inhibited. JQ1 also slows tumor development of an LCL xenograft in immunocompromised mice, but oncogene repression is not observed in endpoint biopsies. We find reduction of EBV-associated lymphoproliferative disease in an animal model encouraging of further studies.
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