University of Texas Southwest Medical Center
Mechanisms of Hepatitis C Virus Persistence.
Hepatitis C virus (HCV) is a global public health threat, and now infects approximately 2-4% of the world population. Of those
people infected with HCV, most will develop a chronic life-long disease that is characterized by persistent virus replication and
progressive liver dysfunction leading to ultimate liver failure. The molecular mechanisms by which HCV mediates persistent
infection are poorly understood, but are thought to be linked to the remarkable ability of the virus to rapidly undergo mutations,
which thereby allow it to adapt to antiviral pressures within the infected cell. My research under the Ellison Medical Foundation
is aimed at understanding how such adaptive mutations within the HCV genome support persistent infection and overall viral
fitness.
Recent work from my laboratory indicates that HCV replication generates double-stranded RNA (dsRNA) products that
stimulate host cell signaling pathways leading to the production of interferon (IFN). IFN triggers the innate cellular antiviral
response, which functions to limit viral replication. Our work suggests that HCV adapts to this IFN pressure by incorporating
mutations that allow it to overcome the IFN-induced antiviral response, and thereby to persist in the infected cell. We now
hypothesize that HCV adaptive mutations may direct specific virus-host interactions that result in suppression of interferon
stimulated genes (ISGs).
To investigate this hypothesis, work will be conducted on three fronts. First, my laboratory will determine how IFN antiviral
pressures within the host cell affects the spectrum of adaptive mutations incorporated into the HCV genome during viral
replication. This work will involve assessing the functional role of specific adaptive mutations in supporting overall viral
replication efficiency within a cell culture model for HCV replication.
Second, we will determine how certain adaptive mutations contribute to viral persistence by directing novel virus-host
interactions that result in suppression of the innate cellular antiviral response. This portion of our work is focused on examining
virus interactions with cellular transcription factors that regulate the statement of ISGs.
Third, we will utilize high-density human genome statement array analysis to determine how adaptive mutations within the
HCV genome ultimately affect the statement of cellular antiviral genes that may otherwise block virus replication.
By directing my laboratory’s research efforts toward a greater understanding of HCV biology and virus-host interactions, I hope
to ultimately identify novel viral and/or cellular targets that will facilitate the therapeutic intervention of HCV infection.
Website: Southwest Medical Center
Contact
Dr. Gale Jr..
Michael
Gale Jr.,
Ph.D.