Regulation of Gammaherpesviral Late Gene Expression

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ABSTRACT Herpesviruses are endemic within the human population, and cause a wide range of life-threatening diseases. Members of the betaherpesvirus and gammaherpesvirus subfamilies are extremely problematic in immunocompromised individuals, leading to severe congenital disorders and a variety of cancers. This proposal will define how a critical class of herpesviral genes are expressed late in the lifecycle of Kaposi's sarcoma-associated herpesvirus (KSHV) through a mechanism that involves a novel transcription complex, which combines both viral mimicry and co-option of select host machinery. The set of viral proteins required for late gene activation are broadly conserved among the beta- and gammaherpesviruses, indicating that information gained herein for KSHV will likely be applicable for Epstein-Barr virus and human cytomegalovirus as well. The focus of this grant is to define the composition and regulation of this novel gene expression complex, and reveal how its function is linked to viral genome replication. Given that even subtle mutations in this late gene transcription complex effectively `kill' the virus, an understanding of its composition and regulation is anticipated to reveal new targets for antiviral strategies.