Gammaherpesviruses infect a majority of humans and are associated with cancer in susceptible populations, including HIV/AIDS patients. A better understanding of the mechanism whereby the host restricts chronic infection is likely to stimulate the development of new therapeutic approaches aimed at decreasing the risk of virus-driven cancer. Here we propose that Ataxia-Telangiectasia mutated (ATM) kinase is an important host factor that regulates chronic gammaherpesvirus infection. We hypothesize that ATM expression by T cells is required for the development of an optimal gammaherpesvirus-specific adaptive immune response. In parallel, ATM is usurped in infected cells to facilitate vira reactivation. These opposing functions establish a virus-host balance that, when perturbed, alters parameters of chronic infection and viral pathogenesis. This hypothesis is supported by our published and preliminary studies and clinical observations indicating that ATM insufficient humans are selectively susceptible to severe herpesvirus infection. The hypothesis will be tested by specific aims that are expected to 1) determine the molecular mechanism by which ATM facilitates gammaherpesvirus reactivation;2) determine the mechanism by which ATM supports the development of virus-specific adaptive immune response, and 3) determine the contribution of ATM to the maintenance of infected cell reservoir during long-term infection. Successful completion of the proposed studies will allow a better insight into the regulation of chronic gammaherpesvirus infection by ATM, an insight that we hope will stimulate new therapeutic approaches aimed to control gammaherpesvirus infection and pathogenesis in at-risk populations, including HIV patients.

Public Health Relevance

A majority of adult population is infected with gammaherpesviruses that are also associated with the development of cancer in susceptible hosts, such as HIV-infected patients. The proposed research aims to identify the mechanism by which ATM regulates chronic gammaherpesvirus infection. The knowledge generated in the course of proposed studies will facilitate the development of new approaches that improve prevention and treatment of gammaherpesvirus-driven cancer.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
Project #
Application #
Study Section
AIDS-associated Opportunistic Infections and Cancer Study Section (AOIC)
Program Officer
Read-Connole, Elizabeth Lee
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Medical College of Wisconsin
Schools of Medicine
United States
Zip Code
Lange, P T; Schorl, C; Sahoo, D et al. (2018) Liver X Receptors Suppress Activity of Cholesterol and Fatty Acid Synthesis Pathways To Oppose Gammaherpesvirus Replication. MBio 9:
Darrah, Eric J; Stoltz, Kyle P; Ledwith, Mitchell et al. (2017) ATM supports gammaherpesvirus replication by attenuating type I interferon pathway. Virology 510:137-146
Darrah, Eric J; Kulinski, Joseph M; Mboko, Wadzanai P et al. (2017) B Cell-Specific Expression of Ataxia-Telangiectasia Mutated Protein Kinase Promotes Chronic Gammaherpesvirus Infection. J Virol 91:
Mboko, Wadzanai P; Rekow, Michaela M; Ledwith, Mitchell P et al. (2017) Interferon Regulatory Factor 1 and Type I Interferon Cooperate To Control Acute Gammaherpesvirus Infection. J Virol 91:
Rekow, Michaela M; Darrah, Eric J; Mboko, Wadzanai P et al. (2016) Gammaherpesvirus targets peritoneal B-1 B cells for long-term latency. Virology 492:140-4
Lange, Philip T; Darrah, Eric J; Vonderhaar, Emily P et al. (2016) Type I Interferon Counteracts Antiviral Effects of Statins in the Context of Gammaherpesvirus Infection. J Virol 90:3342-54
Oleson, Bryndon J; Broniowska, Katarzyna A; Naatz, Aaron et al. (2016) Nitric Oxide Suppresses ?-Cell Apoptosis by Inhibiting the DNA Damage Response. Mol Cell Biol 36:2067-77
Mboko, Wadzanai P; Olteanu, Horatiu; Ray, Avijit et al. (2016) Tumor Suppressor Interferon-Regulatory Factor 1 Counteracts the Germinal Center Reaction Driven by a Cancer-Associated Gammaherpesvirus. J Virol 90:2818-29
Kulinski, Joseph M; Darrah, Eric J; Broniowska, Katarzyna A et al. (2015) ATM facilitates mouse gammaherpesvirus reactivation from myeloid cells during chronic infection. Virology 483:264-74
Cieniewicz, Brandon; Dong, Qiwen; Li, Gang et al. (2015) Murine Gammaherpesvirus 68 Pathogenesis Is Independent of Caspase-1 and Caspase-11 in Mice and Impairs Interleukin-1? Production upon Extrinsic Stimulation in Culture. J Virol 89:6562-74