Herpesviruses are endemic within the human population, and cause a wide range of life-threatening diseases. Members of the beta-herpesvirus (?-HV) and gamma-herpesvirus (?-HV) subfamilies are extremely problematic in immunocompromised individuals, leading to severe congenital disorders and a variety of cancers. During the herpesviral replication cycle, viral genes are expressed temporally in an ordered cascade, with timing linked to appropriate life cycle stage needs. Following viral genome replication, a group of viral genes termed late genes (L) are robustly activated and produce proteins necessary for progeny virion assembly and egress. Mechanisms governing L gene expression in the ?-HV and the ?-HV largely remain a mystery. However, shedding light on this aspect of herpesviral biology has become a high priority, in part due to recent discoveries demonstrating that mutants impaired in this final viral transcription cascade cannot produce progeny virions. An understanding of the regulatory features critical for L gene transcription may therefore reveal robust new targets for antiviral strategies. Our data demonstrate that late gene transcriptional regulation is unique, as it incorporates both molecular mimicry and selective recruitment of key host transcriptional machinery in a manner not previously observed in viral or host gene expression. Thus, the focus of this grant is to define the composition and regulation of this novel gene expression complex, as well as reveal how it may globally impact gene expression in infected cells.
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 a how a viral protein 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|