RESUMEN
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.
Asunto(s)
Antivirales/farmacología , Factores de Transcripción con Cremalleras de Leucina de Carácter Básico/antagonistas & inhibidores , Proteínas del Grupo de Complementación de la Anemia de Fanconi/antagonistas & inhibidores , Regulación Viral de la Expresión Génica/efectos de los fármacos , Herpesvirus Humano 4/efectos de los fármacos , Proteínas Nucleares/antagonistas & inhibidores , Transactivadores/antagonistas & inhibidores , Factores de Transcripción/antagonistas & inhibidores , Proteínas Virales/antagonistas & inhibidores , Acetilación , Azepinas/farmacología , Factores de Transcripción con Cremalleras de Leucina de Carácter Básico/química , Factores de Transcripción con Cremalleras de Leucina de Carácter Básico/genética , Factores de Transcripción con Cremalleras de Leucina de Carácter Básico/metabolismo , Proteínas de Ciclo Celular , Línea Celular , Proteínas del Grupo de Complementación de la Anemia de Fanconi/química , Proteínas del Grupo de Complementación de la Anemia de Fanconi/genética , Proteínas del Grupo de Complementación de la Anemia de Fanconi/metabolismo , Herpesvirus Humano 4/fisiología , Interacciones Huésped-Patógeno/efectos de los fármacos , Humanos , Lisina/metabolismo , Proteínas Nucleares/química , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Dominios y Motivos de Interacción de Proteínas , Procesamiento Proteico-Postraduccional , Transporte de Proteínas/efectos de los fármacos , Interferencia de ARN , Origen de Réplica/efectos de los fármacos , Transactivadores/química , Transactivadores/genética , Transactivadores/metabolismo , Factores de Transcripción/química , Factores de Transcripción/genética , Factores de Transcripción/metabolismo , Triazoles/farmacología , Proteínas Virales/química , Proteínas Virales/genética , Proteínas Virales/metabolismo , Activación Viral/efectos de los fármacos , Fenómenos Fisiológicos de los Virus/efectos de los fármacosRESUMEN
The human Epstein-Barr virus (EBV) evades the immune system by entering a transcriptionally latent phase in B cells. EBV in tumor cells expresses distinct patterns of genes referred to as latency types. Viruses in tumor cells also display varying levels of lytic transcription resulting from spontaneous reactivation out of latency. We measured this dynamic range of lytic transcription with RNA deep sequencing and observed no correlation with EBV latency types among genetically different viruses, but type I cell lines reveal more spontaneous reactivation than isogenic type III cultures. We further determined that latency type and spontaneous reactivation levels predict the relative amount of induced reactivation generated by cytotoxic chemotherapy drugs. Our work has potential implications for personalizing medicine against EBV-transformed malignancies. Identifying latency type or measuring spontaneous reactivation may provide predictive power in treatment contexts where viral production should be either avoided or coerced.