Envelope Proteins Derived from Naturally Integrated Hepatitis B Virus DNA Support Assembly and Release of Infectious Hepatitis Delta Virus Particles

Freitas, Natália; Cunha, Celso; Menne, Stephan; Gudima, Severin O.

doi:10.1128/jvi.00430-14

Cited by 77 publications

(80 citation statements)

References 56 publications

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“…Such proteins could include, e.g., hepadnaviral and lentiviral glycoproteins integrated into the host's genome. In fact, infectious HDV particles can be formed via low-level expression of genome-integrated HBV S-Ag (50). It remains unclear to what degree endogenous viral elements found in animals, plants, and fungi could also contribute to the formation of infectious deltavirus particles and thereby also to their spread.…”

Section: Discussionmentioning

confidence: 99%

Snake Deltavirus Utilizes Envelope Proteins of Different Viruses To Generate Infectious Particles

Szirovicza

Hetzel

Kipar

et al. 2020

mBio

104

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Satellite viruses, most commonly found in plants, rely on helper viruses to complete their replication cycle. The only known example of a human satellite virus is the hepatitis D virus (HDV), and it is generally thought to require hepatitis B virus (HBV) to form infectious particles. Until 2018, HDV was the sole representative of the genus Deltavirus and was thought to have evolved in humans, the only known HDV host. The subsequent identification of HDV-like agents in birds, snakes, fish, amphibians, and invertebrates indicated that the evolutionary history of deltaviruses is likely much longer than previously hypothesized. Interestingly, none of the HDV-like agents were found in coinfection with an HBV-like agent, suggesting that these viruses use different helper virus(es). Here we show, using snake deltavirus (SDeV), that HBV and hepadnaviruses represent only one example of helper viruses for deltaviruses. We cloned the SDeV genome into a mammalian expression plasmid, and by transfection could initiate SDeV replication in cultured snake and mammalian cell lines. By superinfecting persistently SDeV-infected cells with reptarenaviruses and hartmaniviruses, or by transfecting their surface proteins, we could induce production of infectious SDeV particles. Our findings indicate that deltaviruses can likely use a multitude of helper viruses or even viral glycoproteins to form infectious particles. This suggests that persistent infections, such as those caused by arenaviruses and orthohantaviruses used in this study, and recurrent infections would be beneficial for the spread of deltaviruses. It seems plausible that further human or animal disease associations with deltavirus infections will be identified in the future. IMPORTANCE Deltaviruses need a coinfecting enveloped virus to produce infectious particles necessary for transmission to a new host. Hepatitis D virus (HDV), the only known deltavirus until 2018, has been found only in humans, and its coinfection with hepatitis B virus (HBV) is linked with fulminant hepatitis. The recent discovery of deltaviruses without a coinfecting HBV-like agent in several different taxa suggested that deltaviruses could employ coinfection by other enveloped viruses to complete their life cycle. In this report, we show that snake deltavirus (SDeV) efficiently utilizes coinfecting reptarena-and hartmaniviruses to form infectious particles. Furthermore, we demonstrate that cells expressing the envelope proteins of arenaviruses and orthohantaviruses produce infectious SDeV particles. As the envelope proteins are responsible for binding and infecting new host cells, our findings indicate that deltaviruses are likely not restricted in their tissue tropism, implying that they could be linked to animal or human diseases other than hepatitis.

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Section: Discussionmentioning

confidence: 99%

Snake Deltavirus Utilizes Envelope Proteins of Different Viruses To Generate Infectious Particles

Szirovicza

Hetzel

Kipar

et al. 2020

mBio

104

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“…hepadnaviral and lentiviral glycoproteins integrated into the hosts’ genome. In fact, infectious HDV particles can be formed via low level expression of genome-integrated HBV S-Ag 43 . It is tempting to speculate that endogenous viral elements found in animals, plants, and fungi would also contribute to the formation of infectious deltavirus particles and thereby also to their spread.…”

Section: Discussionmentioning

confidence: 99%

Snake deltavirus utilizes envelope proteins of different viruses to generate infectious particles

Szirovicza

Hetzel

Kipar

et al. 2019

Preprint

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2Hepatitis D virus (HDV) is the only known human satellite virus, and it requires hepatitis B virus 3 (HBV) to form infectious particles. Until 2018 HDV was the sole representative of the 4 genus Deltavirus. The subsequent identification of HDV-like agents in non-human hosts indicated a 5 much longer evolutionary history of deltaviruses than previously hypothesized. Interestingly, none 6 of the HDV-like agents were found in co-infection with an HBV-like agent suggesting that these 7 viruses use different helper virus(es). Here we show, using snake deltavirus (SDeV), that HBV 8

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“…An HBV-specific 2.3-kilobase RNA was detected in human hepatoma cell line PLC/PRF/5 which produced HBsAg (Pourcel et al, 1982). In addition, certain HCC cell lines grown in culture that contain integrated HBV DNA can support the production of HBsAg-containing hepatitis D virus (HDV) virions, suggesting that these cells can produce at least low levels of functional HBsAg (Freitas et al, 2014). HBV integrants have also been detected in normal-appearing hepatocytes in both chimpanzees and humans with CHB (Mason et al, 2009(Mason et al, , 2010Tu et al, 2015).…”

Section: Molecular Biology Of Hbv and Its Susceptibility To Rnaimentioning

confidence: 97%

Synthetic RNAi triggers and their use in chronic hepatitis B therapies with curative intent

et al. 2015

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Current therapies for chronic hepatitis B virus infection (CHB) - nucleos(t)ide analogue reverse transcriptase inhibitors and interferons - result in low rates of functional cure defined as sustained off-therapy seroclearance of hepatitis B surface antigen (HBsAg). One likely reason is the inability of these therapies to consistently and substantially reduce the levels of viral antigen production. Accumulated evidence suggests that high serum levels of HBsAg result in exhaustion of the host immune system, rendering it unable to mount the effective antiviral response required for HBsAg clearance. New mechanistic approaches are required to produce high rates of HBsAg seroclearance in order to greatly reduce off-treatment disease progression. Already shown to be a clinically viable means of reducing gene expression in a number of other diseases, therapies based on RNA interference (RNAi) can directly target hepatitis B virus transcripts with high specificity, profoundly reducing the production of viral proteins. The fact that the viral RNA transcripts contain overlapping sequences means that a single RNAi trigger can result in the degradation of all viral transcripts, including all messenger RNAs and pregenomic RNA. Advances in the design of RNAi triggers have increased resistance to degradation and reduced nonspecific innate immune stimulation. Additionally, new methods to effectively deliver the trigger to liver hepatocytes, and specifically to the cytoplasmic compartment, have resulted in increased efficacy and tolerability. An RNAi-based drug currently in clinical trials is ARC-520, a dynamic polyconjugate in which the RNAi trigger is conjugated to cholesterol, which is coinjected with a hepatocyte-targeted, membrane-active peptide. Phase 2a clinical trial results indicate that ARC-520 was well tolerated and resulted in significant, dose-dependent reduction in HBsAg for up to 57days in CHB patients. RNAi-based therapies may play an important role in future therapeutic regimes aimed at improving HBsAg seroclearance and eliminating the need for lifelong therapy. This paper forms part of a symposium in Antiviral Research on "An unfinished story: from the discovery of the Australia antigen to the development of new curative therapies for hepatitis B."

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Envelope Proteins Derived from Naturally Integrated Hepatitis B Virus DNA Support Assembly and Release of Infectious Hepatitis Delta Virus Particles

Cited by 77 publications

References 56 publications

Snake Deltavirus Utilizes Envelope Proteins of Different Viruses To Generate Infectious Particles

Snake Deltavirus Utilizes Envelope Proteins of Different Viruses To Generate Infectious Particles

Snake deltavirus utilizes envelope proteins of different viruses to generate infectious particles

Synthetic RNAi triggers and their use in chronic hepatitis B therapies with curative intent

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