HDV Pathogenesis: Unravelling Ariadne's Thread

Abstract

Hepatitis Delta virus (HDV) lies in between satellite viruses and viroids, as its unique molecular characteristics and life cycle cannot categorize it according to the standard taxonomy norms for viruses. Being a satellite virus of hepatitis B virus (HBV), HDV requires HBV envelope glycoproteins for its infection cycle and its transmission. HDV pathogenesis varies and depends on the mode of HDV and HBV infection; a simultaneous HDV and HBV infection will lead to an acute hepatitis that will resolve spontaneously in the majority of patients, whereas an HDV super-infection of a chronic HBV carrier will mainly result in the establishment of a chronic HDV infection that may progress towards cirrhosis, liver decompensation, and hepatocellular carcinoma (HCC). With this review, we aim to unravel Ariadne's thread into the labyrinth of acute and chronic HDV infection pathogenesis and will provide insights into the complexity of this exciting topic by detailing the different players and mechanisms that shape the clinical outcome.

Keywords: HDV; HDV pathogenesis; acute HDV infection; chronic HDV infection; co-infection; hepatitis B virus HBV; hepatitis Delta virus; super-infection.

Figure 1

HDV-HBV co-infection or HDV super-infection of a chronically infected HBV patient can progress towards viral clearance or chronic infection. Solid arrows demonstrate the major clinical outcome upon co-or super-infection. Created with Servier Medical ART (SMART).

Figure 2

HDV-HBV co-infection will mostly lead to acute hepatitis that is characterised by periods of viral incubation, acute disease, convalescence, and viral resolution. The presence of different serological and biochemical markers characterizes each period. The evolution towards chronic hepatitis is rather rare. Adapted from [15].

Figure 3

HDV superinfection can evolve to (A) acute resolving or (B) acute progressing HDV infection in chronically HBV infected patients. The presence of different HBV and HDV serological and liver biochemical markers coincide with a different phase of the viral replication. While a small number of HDV superinfected patients will resolve HDV infection, the vast majority will progress to CHD, the most severe form of viral hepatitis that can lead to end stage liver diseases. Adapted from [15].

Figure 4

Schematic representation of HDV, HBV and host associated factors that are implicated in HDV pathogenesis.

Figure 5

Schematic representation of HDV interactions with the cell machinery factors implicated on HDV induced pathogenesis. HDV can affect cell cycle regulation of the infected cells (A), mediate epigenetic modifications (B), and activate or downregulate several signalling pathways (C). So far, we do not have detailed information for all the implicated interactions of HDV with the cell machinery components. Created with BioRender.com.

Figure 6

HDV triggers a strong innate immune response in the infected hepatocytes. An unbalanced innate response could contribute to HDV mediated liver immunopathogenesis. (A). HDV active replication induces IFN-β and IFN-λ responses in vitro and in vivo and will induce the production of different ISGs. (B). IFN-α treatment in chronically infected HDV patients was correlated with a loss of terminally differentiated NK cells and an enrichment in immature NK cell subsets. Their role in HDV pathogenesis is still unclear and further studies are required to better decipher their role in HDV pathogenesis. Created with BioRender.com.

Figure 7

Chronic HDV infection induces an adaptive immune response mediated by CD4⁺ and CD8⁺ cytotoxic T cells and MAIT cells, a subset of innate-like T cells. The increased number of cytotoxic CD4⁺ T cells in patients with advanced liver disease represents a critical factor of severe course of viral hepatitis in elderly individuals. Chronic HDV infection can induce the production of HDV specific CD8⁺ CD57^- cytotoxic T cells that contribute to disease progression and memory, such as CD8⁺ T cells, that seem unable to clear viral infection. The role of MAIT cells in HDV pathogenesis needs to be further elucidated, although, it was shown that chronic HDV infection impairs their function. Created with BioRender.com.