Human gammaherpesvirus infection is linked to the development of multiple types of malignancies. These viruses pose a particularly significant risk to immunocompromised patients such as those infected with HIV. Gammaherpesviruses establish stable life-long latent infection in B cells, providing a lifelong reservoir of virus that can eventually contribute to the development of malignant disease. Our long-term goal is to define the mechanisms that gammaherpesviruses use to establish latency in B cells, thereby elucidating new targets for the development of modalities to prevent gammaherpesvirus-associated malignancies. Our approach is to dissect the earliest events of latency establishment using mutant viruses in the murine gammaherpesvirus (gammaHV68, MHV68) system that are unable to undergo lytic replication. By comparing viruses that are mutated in early versus late lytic genes, we have uncovered a surprising role for lytic replication-associated gene products in the establishment of latency in B cells. We hypothesize that these key lytic gene products are critical for the induction of epigenetic modifications that are critical for retention of latent viral episomes. The goals of this proposal are to define the critical molecular events that occur in the earliest hours following B cell infection that ultimately result in stable maintenance of the viral episome during latency. Specifically, we will define the viral transcriptional and genomic events that occur during the establishment phase of B cell latency (Aim 1), we will define the specific late lytic gene that is required for the establishment of stable latency (Aim 2), and we will test the hypothesis that the crucial lytic gene induces epigenetic modifications that are critical for latency establishment in B cells. The proposed studies should provide significant new insight into the critical molecular events that occur during the earliest moments of gammaherpesvirus infection of B cells.

Public Health Relevance

Epstein-Barr virus and Kaposi's sarcoma-associated herpesvirus infections are linked to the development of numerous types of cancers, and pose a particularly significant risk to AIDS patients and transplant recipients. The proposed research will examine the events that occur in the earliest stages of infection in an effort to gain new insight into the means by which these viruses establish lifelong infections. This work has important implications for the development of drugs to prevent or treat virus-associated cancers.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA139984-05
Application #
8607146
Study Section
AIDS-associated Opportunistic Infections and Cancer Study Section (AOIC)
Program Officer
Read-Connole, Elizabeth Lee
Project Start
2010-02-01
Project End
2015-01-31
Budget Start
2014-02-01
Budget End
2015-01-31
Support Year
5
Fiscal Year
2014
Total Cost
$265,382
Indirect Cost
$84,234
Name
University of Florida
Department
Genetics
Type
Schools of Medicine
DUNS #
969663814
City
Gainesville
State
FL
Country
United States
Zip Code
32611