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.
Kaposi's sarcoma-associated herpesvirus (KSHV) is an emerging Group 1 pathogen and the major cause of cancers in untreated AIDS patients. KSHV, like other DNA viruses, expresses a class of genes late during infection that are essential for viral assembly and escape from their host cell, but how the expression of these genes is regulated has long remained unknown. This grant is focused on revealing how a group of KSHV proteins orchestrates this process though a combination of molecular mimicry and co-option of host gene expression machinery.
|Gardner, Matthew R; Glaunsinger, Britt A (2018) Kaposi's Sarcoma-Associated Herpesvirus ORF68 Is a DNA Binding Protein Required for Viral Genome Cleavage and Packaging. J Virol 92:|
|Hesser, Charles R; Karijolich, John; Dominissini, Dan et al. (2018) N6-methyladenosine modification and the YTHDF2 reader protein play cell type specific roles in lytic viral gene expression during Kaposi's sarcoma-associated herpesvirus infection. PLoS Pathog 14:e1006995|
|Davis, Zoe H; Hesser, Charles R; Park, Jimin et al. (2016) Interaction between ORF24 and ORF34 in the Kaposi's Sarcoma-Associated Herpesvirus Late Gene Transcription Factor Complex Is Essential for Viral Late Gene Expression. J Virol 90:599-604|