Sodium taurocholate cotransporting polypeptide is the limiting host factor of hepatitis B virus infection in macaque and pig hepatocytes

Lempp, Florian A.; Wiedtke, Ellen; Qu, Bingqian; Roques, Pierre; Chemin, Isabelle; Vondran, Florian W. R.; Grand, Roger Le; Grimm, Dirk; Urban, Stephan

doi:10.1002/hep.29112

Cited by 82 publications

(87 citation statements)

References 39 publications

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“…Currently, primary human hepatocytes (PHHs) (Lempp et al, 2017;Ni and Urban, 2017;Shimura et al, 2017), HepaRG cells (Gripon et al, 2002;Schulze et al, 2012), and primary tupia hepatocytes (PTHs) (Kock et al, 2001;Ren and Nassal, 2001) are the main cell models used to study the early steps of HBV infection. PHHs, the natural host of HBV, are regarded as the ideal cellular model for HBV infection.…”

Section: Introductionmentioning

confidence: 99%

Productive HBV infection of well-differentiated, hNTCP-expressing human hepatoma-derived (Huh7) cells

et al. 2017

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Feasible and effective cell models for hepatitis B virus (HBV) infection are required for investigating the complete lifecycle of this virus, including the early steps of viral entry. Resistance to dimethyl sulfoxide/polyethylene glycol (DMSO/PEG), hNTCP expression, and a differentiated state are the limiting factors for successful HBV infection models. In the present study, we used a hepatoma cell line (Huh7D hNTCP ) to overcome these limiting factors so that it exhibits excellent susceptibility to HBV infection. To achieve this goal, different hepatoma cell lines were tested with 2.5% DMSO / 4% PEG8000, and one resistant cell line (Huh7D) was used to construct a stable hNTCP-expressing cell line (Huh7D hNTCP ) using a recombinant lentivirus system. Then, the morphological characteristics and differentiation molecular markers of Huh7D hNTCP cells with or without DMSO treatment were characterized. Finally, the susceptibility of Huh7D hNTCP cells to HBV infection was assessed. Our results showed that Huh7D cells were resistant to 2.5% DMSO / 4% PEG8000, whereas the others were not. Huh7D hNTCP cells were established to express a high level of hNTCP compared to liver extracts, and Huh7D hNTCP cells rapidly transformed into a non-dividing, well-differentiated polarized phenotype under DMSO treatment. Huh7D hNTCP cells fully supported the entire lifecycle of HBV infection. This cell culture system will be useful for the analysis of host-virus interactions, which should facilitate the discovery of antiviral drugs and vaccines.

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Section: Introductionmentioning

confidence: 99%

Productive HBV infection of well-differentiated, hNTCP-expressing human hepatoma-derived (Huh7) cells

et al. 2017

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“…Human NTCP as well as the rat, mouse, and dog orthologs efficiently bound Myrcludex‐B, while macaque and pig NTCP did not. However, only hNTCP was able to confer efficient HBV and HDV infection . Taken together these data suggest that only hNTCP is able to confer HBV and HDV entry and that hepatocytes from distinct species lack an additional essential entry factor or express a species‐specific restriction factor.…”

Section: Features Of Hbv and Hdv Infection In Primary Hepatocytes Fromentioning

confidence: 77%

“…A key finding of this study is the observation that primary hepatocytes from macaque (cynomolgus and rhesus) and pig become fully susceptible to both HDV and HBV infection when transcomplemented with hNTCP . Although viral replication appeared to be lower than in human hepatocytes, it was robustly detectable including formation of covalently closed circular DNA .…”

Section: Features Of Hbv and Hdv Infection In Primary Hepatocytes Fromentioning

confidence: 81%

“…In this issue of Hepatology , Lempp and colleagues from Stephan Urban's laboratory at the University of Heidelberg/German Center for Infection Research advance the knowledge of the function of NTCP as a species‐specific HBV/HDV entry factor by studying how overexpression of hNTCP promotes HBV and HDV infection in primary hepatocytes from different animal species . First, the authors demonstrate that hNTCP overexpression allows efficient binding of Myrcludex‐B, a myristoylated peptide derived from the pre‐S1 domain of the HBV large surface protein.…”

Section: Features Of Hbv and Hdv Infection In Primary Hepatocytes Fromentioning

confidence: 99%

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Toward novel immunocompetent animal models for hepatitis B virus infection

2017

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“…In vitro studies have suggested that hNTCP expression in primary hepatocytes from cynomolgus macaques, rhesus macaques, and pigs render these cells susceptible to hepatitis delta virus (HDV) and presumably HBV infection and replication . This concept was recently tested in vivo for macaques.…”

Section: Discussionmentioning

confidence: 99%

Woolly Monkey–HBV Infection in Squirrel Monkeys as a Surrogate Nonhuman Primate Model of HBV Infection

et al. 2020

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Development of curative therapies for chronic hepatitis B virus (HBV) infection will likely require new animal models. Here, we evaluate HBV infection in squirrel monkeys based on the high‐sequence homology of the HBV receptor, Na+/taurocholate co‐transporting peptide (NTCP), between humans and squirrel monkeys. HBV PreS1 peptide was examined for binding human and squirrel monkey NTCP. Immunodeficient Fah−/−, NOD, Rag1−/−, Il2Rgnull (FNRG) mice engrafted with human or squirrel monkey hepatocytes were challenged with HBV or Woolly Monkey HBV (WMHBV). In addition, adult squirrel monkeys were inoculated with HBV, WMHBV, adeno‐associated virus containing an infectious genome of HBV (AAV‐HBV), and AAV‐WMHBV. Finally, neonate squirrel monkeys were assessed for the potential of chronic infection with WMHBV. PreS1 peptide efficiently bound to human and squirrel monkey NTCP but not to mouse or capuchin NTCP. FNRG mice engrafted with squirrel monkey hepatocytes were susceptible to infection by WMHBV but not human HBV. Similarly, adult squirrel monkeys could be infected with WMHBV but not human HBV, whereas chimeric mice engrafted with human hepatocytes were susceptible to HBV but not WMHBV. Infection of squirrel monkeys with AAV‐WMHBV yielded maximum viremia of 108 genomes/mL with detectable virus for up to 8 months. Notably, covalently closed circular DNA was detected in the liver of these animals. Infection of neonates with WMHBV led to detectable viremia for up to 6 months. Conclusions: Adult and neonate squirrel monkeys exhibited prolonged WMHBV viremia lasting 6‐8 months. This is greater than twice the duration of viremia achieved in other nonhuman primates and suggests that squirrel monkeys may be a suitable model for testing HBV therapeutics.

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Sodium taurocholate cotransporting polypeptide is the limiting host factor of hepatitis B virus infection in macaque and pig hepatocytes

Cited by 82 publications

References 39 publications

Productive HBV infection of well-differentiated, hNTCP-expressing human hepatoma-derived (Huh7) cells

Productive HBV infection of well-differentiated, hNTCP-expressing human hepatoma-derived (Huh7) cells

Toward novel immunocompetent animal models for hepatitis B virus infection

Woolly Monkey–HBV Infection in Squirrel Monkeys as a Surrogate Nonhuman Primate Model of HBV Infection

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