Molecular and clinical aspects of hepatitis D virus infections

Abstract

Hepatitis D virus (HDV) is a defective virus with circular, single-stranded genomic RNA which needs hepatitis B virus (HBV) as a helper virus for virion assembly and infectivity. HDV virions are composed of a circular shape HDV RNA and two types of viral proteins, small and large HDAgs, surrounded by HBV surface antigen (HBsAg). The RNA polymerase II from infected hepatocytes is responsible for synthesizing RNAs with positive and negative polarities for HDV, as the virus does not code any enzyme to replicate its genome. HDV occurs as co-infection or super-infection in up to 5% of HBsAg carriers. A recent multi-center study highlighted that pegylated interferon α-2a (PEG-IFN) is currently the only treatment option for delta hepatitis. Nucleotide/nucleoside analogues, which are effective against HBV, have no relevant effects on HDV. However, additional clinical trials combining PEG-IFN and tenofovir are currently ongoing. The molecular interactions between HDV and HBV are incompletely understood. Despite fluctuating patterns of HBV viral load in the presence of HDV in patients, several observations indicate that HDV has suppressive effects on HBV replication, and even in triple infections with HDV, HBV and HCV, replication of both concomitant viruses can be reduced. Additional molecular virology studies are warranted to clarify how HDV interacts with the helper virus and which key cellular pathways are used by both viruses. Further clinical trials are underway to optimize treatment strategies for delta hepatitis.

Keywords: Delta hepatitis; Hepatitis B virus; Hepatitis B virus surface antigen; Hepatitis D virus; Hepatocellular carcinoma; Liver cirrhosis.

Figure 1

Hepatitis D virus life cycle in hepatocytes in the presence of hepatitis B virus. Schematic summary of the current concept of hepatitis D virus (HDV) replication cycle. The entry of HDV particles into hepatocytes is mediated by the attachment of hepatitis B virus (HBV) surface antigens coating HDV nucleoprotein to the host cell receptors, followed by endocytosis and uncoating of the virions (1). HDV nucleoprotein complex is leaded to the nucleus by accompanying S-HDAg, then the complex arrives to the nucleolus where RNA Pol I exists (2). Multimeric full-length antigenomic RNAs (AG-RNAs) are transcribed from HDV genomic RNA, likely by RNA Pol I. Circular AG-RNA molecules which are created by ribozyme activities of AG-RNA itself move to the nucleoplasm (3). AG-Strands serve as templates for RNA Pol II (4). RNA Pol II starts generating mRNA from genomic strands (5a) and full-length transcripts from AG-strands (5b). 6: Due to RNA editing at position 1012 of S-HDAg exerted by double-stranded RNA-specific adenosine deaminase, the open reading frame of these mRNA molecules extends for additional 19 amino acids, which lead to the production of Large delta antigen (6). mRNA molecules coding for small and large delta antigens move to the cytoplasm and are translated to relevant proteins (7,8). Small delta antigens activate genomic RNA replication (7), while large proteins promote virion assembly (8). Viral proteins form nucleoprotein complexes with HDV genomic RNAs (9). L-HDAg in HDV ribonucleoprotein complex interacts with existing HBV surface proteins in the cell (10). After HDV encapsidation by HBV surface proteins (11), complete virions leave the cell through exocytosis (12). HBV surface proteins bud through the endoplasmic reticulum or golgi body membranes of the host cell (A).