HDV RNA replication is associated with HBV repression and interferon-stimulated genes induction in super-infected hepatocytes

Abstract

Hepatitis D virus (HDV) super-infection of Hepatitis B virus (HBV)-infected patients is the most aggressive form of viral hepatitis. HDV infection is not susceptible to direct anti-HBV drugs, and only suboptimal antiviral responses are obtained with interferon (IFN)-alpha-based therapy. To get insights on HDV replication and interplay with HBV in physiologically relevant hepatocytes, differentiated HepaRG (dHepaRG) cells, previously infected or not with HBV, were infected with HDV, and viral markers were extensively analyzed. Innate and IFN responses to HDV were monitored by measuring pro-inflammatory and interferon-stimulated gene (ISG) expression. Both mono- and super-infected dHepaRG cells supported a strong HDV intracellular replication, which was accompanied by a strong secretion of infectious HDV virions only in the super-infection setting and despite the low number of co-infected cells. Upon HDV super-infection, HBV replication markers including HBeAg, total HBV-DNA and pregenomic RNA were significantly decreased, confirming the interference of HDV on HBV. Yet, no decrease of circular covalently closed HBV DNA (cccDNA) and HBsAg levels was evidenced. At the peak of HDV-RNA accumulation and onset of interference on HBV replication, a strong type-I IFN response was observed, with interferon stimulated genes, RSAD2 (Viperin) and IFI78 (MxA) being highly induced. We established a cellular model to characterize in more detail the direct interference of HBV and HDV, and the indirect interplay between the two viruses via innate immune responses. This model will be instrumental to assess molecular and immunological mechanisms of this viral interference.

HDV infection in immigrant populations

“…111 Little data have been published on the virological characteristics of HDV-infected immigrants. As expected from the well-known interaction between the two viruses, 126 Rivas et al 124 HBsAg serum levels were lower in HDV-coinfected than in HBV-…”

“…Little data have been published on the virological characteristics of HDV‐infected immigrants. As expected from the well‐known interaction between the two viruses, Rivas et al showed that the median serum HBV DNA was significantly lower in HDV‐positive than ‐negative patients. Similarly, Heidrich et al demonstrated that both the HBV‐DNA positivity rate (29% vs 53%, P < .001) and HBsAg serum levels were lower in HDV‐coinfected than in HBV‐monoinfected.…”

“…More recently, of the 104 HIV/HBV/HDV coinfected patients included in the Swiss HIV Cohort, 27% were immigrants from Southern Europe, sub‐Saharan Africa, or southeast Asia.…”

Interplay between the Hepatitis B Virus and Innate Immunity: From an Understanding to the Development of Therapeutic Concepts

“…In contrast to HDV [47,48], HBV infections seem to be associated with a lack of induction or even a decreased expression of ISGs or other pro-inflammatory genes, thus pointing toward mechanisms of active inhibition. The first demonstration that HBV could inhibit PRR signaling pathways came from a study, which showed that both HBeAg and HBsAg could antagonize the antiviral action of PRR agonists in murine parenchymal and non-parenchymal cells [49].…”

“…It seems appropriate to indicate that if the HBV-driven strategies to inhibit immune responses are genuine, they are only adapted to what HBV itself would be able to trigger as a weak inducer of innate responses; indeed, it seems that HBV-mediated inhibitory phenotypes are not very potent and are likely not capable of fully counteracting a more aggressive induction of innate responses, like that mediated, for instance, by HDV [48]. …”