Unorthodox transmission mode of delta viruses in nature

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Hepatitis delta virus (HDV) is the smallest RNA pathogen known to interact with human hosts and causes substantial global morbidity and mortality. Strikingly, it lacks the ability to produce its own envelope surface proteins and is thus dependent on the presence of a helper virus, which provides its surface proteins to produce infectious and transmissible particles. For decades, HDV has been associated only with hepatitis B virus (HBV) as helper virus providing the viral envelope proteins, which leads to a more severe liver disease than chronic HBV mono-infection, with an increased risk of cirrhosis and pejorative evolution (1).

We discovered that HDV can indeed use envelope glycoproteins from diverse viruses, among which hepatitis C virus, Dengue virus or West Nile virus, to produce infectious particles in tissue culture (2). Furthermore, we demonstrated that HCV can propagate HDV infection in the liver of co-infected humanized mice.

This study therefore questioned the relevance of these results in nature.

Interestingly, previous to our work, the presence of HDV antigen and RNA had been reported in salivary glands of primary Sjögren’s syndrome patients in the absence of HBsAg or HBV antibodies (3). In addition, in parallel to our study, HDV-like sequences were identified in a variety of animals and insects; yet, these sequences were detected in absence of HBV infection (4-8). A further study then showed that deltaviruses from snakes can produce infectious particle by using envelope protein from arenaviruses and orthohantaviruses (9).

Finally, three clinical studies have now been performed in order to provide proofs for HDV infection in patients only co-infected with HCV (10-12), highlighting in one study a preliminary evidence of HDV exposure in chronically HCV-infected patients in the absence of ongoing or past HBV infection (12).

Altogether, these studies now raise several questions concerning the immunological and virologic relations between HDV and HBV or alternative helper viruses, the origin and evolution of HDV and deltaviruses, and the exact pathogenesis and tissue tropism of HDV. Perhaps one of the most important question is if HDV can be transmitted in humans by other helper viruses than HBV. And if HDV has a wider range of potential coinfections than previously thought, what could be the clinical relevance and pathobiological implications?


Jimena Pérez-Vargas and François-Loïc Cosset

 CIRI - Centre International de Recherche en Infectiologie, Univ Lyon, Ecole Normale Supérieure de Lyon, Université de Lyon-1, Inserm U1111, CNRS UMR5308, Lyon, France


Literature cited: 

  1. Wedemeyer H, Manns MP. Epidemiology, pathogenesis and management of hepatitis D: update and challenges ahead. Nat Rev Gastroenterol Hepatol 2010;7:31-40.
  2. Perez-Vargas J, Amirache F, Boson B, Mialon C, Freitas N, Sureau C, Fusil F, et al. Enveloped viruses distinct from HBV induce dissemination of hepatitis D virus in vivo. Nat Commun 2019;10:2098.
  3. Weller ML, Gardener MR, Bogus ZC, Smith MA, Astorri E, Michael DG, Michael DA, et al. Hepatitis Delta Virus Detected in Salivary Glands of Sjogren's Syndrome Patients and Recapitulates a Sjogren's Syndrome-Like Phenotype in Vivo. Pathog Immun 2016;1:12-40.
  4. Paraskevopoulou S, Pirzer F, Goldmann N, Schmid J, Corman VM, Gottula LT, Schroeder S, et al. Mammalian deltavirus without hepadnavirus coinfection in the neotropical rodent Proechimys semispinosus. Proc Natl Acad Sci U S A 2020;117:17977-17983.
  5. Bergner LM, Orton RJ, Broos A, Tello C, Becker DJ, Carrera JE, Patel AH, et al. Satellite virus diversification through host shifting revealed by novel deltaviruses in vampire bats. bioRxiv 2020:2020.2006.2017.156745.
  6. Chang W, Pettersson J-O, Le Lay C, Shi M, Lo N, Wille M, Eden J, et al. Novel hepatitis D-like agents in vertebrates and invertebrates. bioRxiv 2019;
  7. Hetzel U, Szirovicza L, Smura T, Prahauser B, Vapalahti O, Kipar A, Hepojoki J. Identification of a Novel Deltavirus in Boa Constrictors. MBio 2019;10.
  8. Wille M, Netter HJ, Littlejohn M, Yuen L, Shi M, Eden JS, Klaassen M, et al. A Divergent Hepatitis D-Like Agent in Birds. Viruses 2018;10.
  9. Szirovicza L, Hetzel U, Kipar A, Martinez-Sobrido L, Vapalahti O, Hepojoki J. Snake deltavirus utilizes envelope proteins of different viruses to generate infectious particles. bioRxiv 2019:698514.
  10. Cappy P, Lucas Q, Kankarafou N, Sureau C, Laperche S. No Evidence of HCV-Assisted HDV Propagation in a Large Cohort of Hepatitis C Positive Blood Donors. J Infect Dis 2020.
  11. Pfluger LS, Schulze Zur Wiesch J, Polywka S, Lutgehetmann M. Hepatitis delta virus propagation enabled by hepatitis C virus-Scientifically intriguing, but is it relevant to clinical practice? J Viral Hepat 2021;28:213-216.
  12. Chemin I, Pujol FH, Scholtes C, Loureiro CL, Amirache F, Levrero M, Zoulim F, et al. Preliminary evidence for hdv exposure in apparently non-HBV-infected patients. Hepatology 2020.


François-Loïc Cosset

Scientist, CIRI - International Center for Infectiology Research