Hepatitis Delta Virus and Hepatocellular Carcinoma

Abstract

The hepatitis D virus (HDV) is a compact, enveloped, circular RNA virus that relies on hepatitis B virus (HBV) envelope proteins to initiate a primary infection in hepatocytes, assemble, and secrete new virions. Globally, HDV infection affects an estimated 12 million to 72 million people, carrying a significantly elevated risk of developing cirrhosis, liver failure, and hepatocellular carcinoma (HCC) compared to an HBV mono-infection. Furthermore, HDV-associated HCC often manifests at a younger age and exhibits more aggressive characteristics. The intricate mechanisms driving the synergistic carcinogenicity of the HDV and HBV are not fully elucidated but are believed to involve chronic inflammation, immune dysregulation, and the direct oncogenic effects of the HDV. Indeed, recent data highlight that the molecular profile of HCC associated with HDV is unique and distinct from that of HBV-induced HCC. However, the question of whether the HDV is an oncogenic virus remains unanswered. In this review, we comprehensively examined several crucial aspects of the HDV, encompassing its epidemiology, molecular biology, immunology, and the associated risks of liver disease progression and HCC development.

Keywords: HBV; HCC; HDV; chronic hepatitis; cirrhosis; liver disease.

Figure 1

Schematic representation of HDV viral particle. Abbreviations: HBsAg (hepatitis B surface antigen); L-HDAg (large-hepatitis delta antigen); S-HDAg (small-hepatitis delta antigen); -ssRNA (negative single-stranded RNA). Created using BioRender.com.

Figure 2

Life cycle of HDV. (1) The virus binds to the NTCP membrane receptor by the envelope composed of HBV HBsAgs. The viral particle then enters the cell through endocytosis, and the viral ribonucleoprotein is released into the cytoplasm. (2) The L- and S-HDAgs contain a nuclear localization signal that leads to the translocation of the viral ribonucleoprotein into the nucleus. (3) Here, the transcription of HDAg mRNA occurs via recruitment by the cellular RNA polymerase II. The HDAg mRNA is then exported to the cytoplasm, where it is translated to produce S-HDAgs. (4) During the first phase of replication, the HDV genomic RNA serves as a template to produce antigenomic RNA via RNA polymerase I. (5) The antigenomic RNA is then used by RNA polymerase II to produce new genomic RNAs. (6) The antigenomic RNA is also modified by the ADAR1 enzyme, which leads to the elimination of the stop codon of the S-HDAg. (7) The modified antigenomic RNA is replicated into the genomic RNA, thus inducing the transcription of the modified HDAg mRNA, which is exported to the cytoplasm, where this time, it leads to the production of the L-HDAg protein. (8) The L-HDAg contains a prenylation site that is farnesylated by a cellular farnesyltransferase before being translocated to the nucleus. (9) Both forms of the HDAg interact with the newly synthesized genomic RNA to form new viral ribonucleoproteins (RNPs) that are exported to the cytoplasm. (10) The L-HDAg, through its farnesylated cysteine, interacts with the cytosolic part of the HBsAg on the surface of the endoplasmic reticulum, thus inducing viral RNPs envelopment. (11) Enveloped viral particles are subsequently secreted through the endoplasmic reticulum (ER)–Golgi secretory pathway. (12) HDV virions exit the infected cell. The figure represents a cell infected with HBV, represented by the presence of cccDNA and the transcription of mRNA that lead to the translation of the HBsAgs necessary for the formation of the HDV envelope. Created using BioRender.com.

Figure 3

Schematic representation of the mechanisms by which HDV potentially induces HCC. The main downregulated pathways involved are as follows: hepatic fbrosis and hepatic stellate cell activation, while the most upregulated pathways are: Hedgehog signaling, GADD45, DNA damage-induced 14-3-3σ signaling, cyclins and cell cycle regulation, G2/M DNA damage, checkpoint regulation, and hereditary breast cancer. Created using BioRender.com.