Research Projects

Direct-acting antivirals (DAAs) against hepatitis C virus (HCV) could eliminate virus, but some molecular changes persist in HCV-cured patients, which increases the risk of hepatic complications that leads to hepatocellular carcinoma. Additionally, elimination of occult HCV from infected tissue is another challenge to global HCV eradication plan by 2030. Thus, developing adjunctive therapies with DAA to prevent HCV-induced pathogenesis in addition to viral clearance including occult infection, is of utmost importance. Host RNA binding proteins (RBPs) are implicated in viral infection as well as cellular changes associated with pathogenesis. Post-translational modifications upon infection with different genotypes of HCV could differentially regulate the subcellular localization and RBP function, in establishing viral infection or mediating cellular pathogenesis. We are studying the role of RBPs in RNA virus infection for past three decades and showed how several host factors (primarily RBPs) are exploited for viral RNA replication and translation. Recently we demonstrated how cytoplasmic abundance of a critical host factor HuR protein (an RBP) is modulated by the viral protein (NS3) that triggers a cellular kinase (PKC delta) leading to phosphorylation at a specific site (Raheja et al, 2023). Deciphering precise role of RBP modifications that mediates cellular pathogenesis could unravel novel targets. Further, HCV induced oxidative stress leads to liver injury and the extent of liver damage varies with the infecting genotype. Chronic Hepatitis C (CHC) infection can induce iron overload, potentially causing ferroptosis, that leads to ROS generation, mitochondrial dysfunction and concomitant oxidative stress, which are central to disease progression. Thus, a systematic comparative study pan-genotype would be important for better understanding of the disease dynamics. We hypothesize that HCV infection with different genotypes could lead to differential oxidative stress followed by differential post-translational modifications of cellular RBPs, altering their targets and functions, contributing to cellular pathogenesis. Alternatively, HCV infection with different genotypes could induce differential post-translational modification in RBPs by cellular enzymes, altering RBP targets/functions that trigger ROS generation, leading to mitochondrial dysfunction and oxidative stress to different extents and contribute to differential pathogenesis. Oxidative stress could be the cause or consequence of RBP modifications. Thus, we would like to investigate the RBPs involved in HCV induced pathogenesis and their role in triggering oxidative stress and mitochondrial dysfunction. Finally, we would explore small molecule inhibitors which inhibit RBP modifications and functions, in reducing oxidative stress to prevent pan-genotype pathogenesis. The knowledge generated will drive the field to new directions for exploring more personalized strategies.