Hepatitis Delta Virus Alters the Autophagy Process To Promote Its Genome Replication
| Autor: | Marwa Khabir, Matthieu Blanchet, Camille Sureau, Patrick Labonté, Asma Zahra Aliche |
|---|---|
| Rok vydání: | 2019 |
| Předmět: |
HBsAg
Hepatitis B virus viruses Immunology ATG5 Biology medicine.disease_cause Virus Replication Microbiology Virus Defective virus Cell Line 03 medical and health sciences Virology medicine Autophagy Humans 030304 developmental biology Hepatitis delta Antigens 0303 health sciences Hepatitis B Surface Antigens Coinfection 030302 biochemistry & molecular biology virus diseases Hep G2 Cells biochemical phenomena metabolism and nutrition biology.organism_classification Hepatitis B digestive system diseases Hepatitis D 3. Good health Virus-Cell Interactions HEK293 Cells Viral replication Liver Insect Science RNA Viral Satellite (biology) Hepatitis Delta Virus |
| Zdroj: | J Virol |
| ISSN: | 1098-5514 |
| Popis: | A substantial number of viruses have been demonstrated to subvert autophagy to promote their own replication. Recent publications have reported the proviral effect of autophagy induction on hepatitis B virus (HBV) replication. Hepatitis delta virus (HDV) is a defective virus and an occasional obligate satellite of HBV. However, no previous work has studied the relationship between autophagy and HDV. In this article, we analyze the impact of HBV and HDV replication on autophagy as well as the involvement of the autophagy machinery in the HDV life cycle when produced alone and in combination with HBV. We prove that HBxAg and HBsAg can induce early steps of autophagy but ultimately block flux. It is worth noting that the two isoforms of the HDV protein, the small HDAg (S-HDAg) and large HDAg (L-HDAg) isoforms, can also efficiently promote autophagosome accumulation and disturb autophagic flux. Using CRISPR-Cas9 technology to generate specific knockouts, we demonstrate that the autophagy machinery, specifically the proteins implicated in the elongation step (ATG7, ATG5, and LC3), is important for the release of HBV without affecting the level of intracellular HBV genomes. Surprisingly, the knockout of ATG5 and ATG7 decreased the intracellular HDV RNA level in both Huh7 and HepG2.2.15 cells without an additional effect on HDV secretion. Therefore, we conclude that HBV and HDV have evolved to utilize the autophagy machinery so as to assist at different steps of their life cycle. IMPORTANCE Hepatitis delta virus is a defective RNA virus that requires hepatitis B virus envelope proteins (HBsAg) to fulfill its life cycle. Thus, HDV can only infect individuals at the same time as HBV (coinfection) or superinfect individuals who are already chronic carriers of HBV. The presence of HDV in the liver accelerates the progression of infection to fibrosis and to hepatic cancer. Since current treatments against HBV are ineffective against HDV, it is of paramount importance to study the interaction between HBV, HDV, and host factors. This will help unravel new targets whereby a therapy that is capable of simultaneously impeding both viruses could be developed. In this research paper, we evidence that the autophagy machinery promotes the replication of HBV and HDV at different steps of their life cycle. Notwithstanding their contribution to HBV release, autophagy proteins seem to assist HDV intracellular replication but not its secretion. |
| Databáze: | OpenAIRE |
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