Prof Anna Kramvis
- Hepatitis Virus Diversity Research Unit, Department of Internal Medicine, University of the Witwatersrand
Title of the project
Physical Properties of Core and HBeAg/Precursors and Host-Pathogen Interactions Leading to Development of Hepatocellular Carcinoma.
Hepatitis B virus (HBV) infection is a major cause of acute and chronic hepatitis, liver cirrhosis and hepatocellular carcinoma (HCC) worldwide. Over 250 million chronically infected carriers are at high risk of complications from cirrhosis and primary liver cancer. Two viral proteins, very similar but having different roles during infection, could be implicated in the development of liver cancer: core protein, the capsid protein, and HBeAg, a non-particulate, secreted protein. The role of Hepatitis B e Antigen (HBeAg) in the viral life cycle has not been fully elucidated, although it is known to be required for infection in vivo and for persistence, because this protein acts as tolerogen. HBeAg is translated as a precore/core protein and undergoes several post-translational modifications. A G1862T HBV mutant is frequently isolated from HCC patients infected with subgenotype A1, the only strain of HBV, which develops this mutation. Moreover, subgenotype A1 has been shown to have a higher hepatocarcinogenic potential than other genotypes/ subgenotypes of HBV. Among the HBV carriers, 7%-30% are infected with HBV variants that express little or no hepatitis B e antigen. On the other hand, HBeAg and its precursors may promote the progress of HCC by interactions with different host proteins. This project will focus on characterizing the physical properties of HBeAg/precursors and core protein, as they contain an intrinsic disordered region (IDR), very common in oncogenes and processes of carcinogenesis. It has been shown in the recent literature that the IDR of RNA-binding proteins can phase separately to form liquid droplets, a process by which cells can establish ribonucleoprotein particles leading to their pathogenicity. The second part of the project will focus on the host response and pathways linked to the expression of HBeAg and implicated in the process of carcinogenesis.