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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI122528-04
Application #
9590145
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Beisel, Christopher E
Project Start
2015-11-13
Project End
2020-10-31
Budget Start
2018-11-01
Budget End
2019-10-31
Support Year
4
Fiscal Year
2019
Total Cost
Indirect Cost
Name
University of California Berkeley
Department
Other Basic Sciences
Type
Earth Sciences/Resources
DUNS #
124726725
City
Berkeley
State
CA
Country
United States
Zip Code
94704