Highly diversified shrew hepatitis B viruses corroborate ancient origins and divergent infection patterns of mammalian hepadnaviruses

Rasche, Andrea; Lehmann, Felix; König, Alexander; Goldmann, Nora; Corman, Victor M.; Moreira-Soto, Andrés; Geipel, Andreas; Riel, Debby van; Vakulenko, Yulia A.; Sander, Anna-Lena; Niekamp, Hauke; Kepper, Ramona; Schlegel, Mathias; Akoua‐Koffi, Chantal; Souza, Breno F C D; Sahr, Foday; Olayemi, Ayodeji; Schulze, Vanessa; Petraitytė-Burneikienė, Rasa; Kazāks, Andris; Lowjaga, Kira Alessandra Alicia Theresa; Geyer, Joachim; Kuiken, Thijs; Drosten, Christian; Lukashev, Alexander N.; Fichet‐Calvet, Elisabeth; Ulrich, Rainer G.; Glebe, Dieter; Drexler, Jan Felix

doi:10.1073/pnas.1908072116

Cited by 19 publications

(28 citation statements)

References 41 publications

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“…Publicly available sequence information may not contain adequate information on time of isolation and recombinant sequences can affect evolutionary reconstructions ( Rasche et al 2019 ). Using all publicly available sequences, temporal analyses of HCoV phylogenies ( Fig.…”

Section: Resultsmentioning

confidence: 99%

The evolutionary dynamics of endemic human coronaviruses

Drosten

Drexler

2021

Virus Evolution

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Community protective immunity can affect RNA virus evolution by selecting for new antigenic variants on the scale of years, exemplified by the need of annual evaluation of influenza vaccines. The extent to which this process termed antigenic drift affects coronaviruses remains unknown. Alike the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), seasonal human coronaviruses (HCoV) likely emerged from animal reservoirs as new human pathogens in the past. We therefore analyzed the long-term evolutionary dynamics of the ubiquitous HCoV-229E and HCoV-OC43 in comparison with human influenza A virus (IAV) subtype H3N2. We focus on viral glycoprotein genes that mediate viral entry into cells and are major targets of host neutralizing antibody responses. Maximum likelihood and Bayesian phylogenies of publicly available gene datasets representing about three decades of HCoV and IAV evolution showed that all viruses had similar ladder-like tree shapes compatible with antigenic drift, supported by different tree shape statistics. Evolutionary rates inferred in a Bayesian framework were 6.5 × 10−4 (95% HPD, 5.4–7.5 × 10−4) substitutions per site per year (s/s/y) for HCoV-229E spike (S) genes and 5.7x10−4 (95% HPD, 5–6.5 × 10−4) s/s/y for HCoV-OC43 S genes, which were about 4-fold lower than the 2.5x10−3 (95% HPD, 2.3–2.7 × 10−3) s/s/y rate for IAV hemagglutinin (HA) genes. Coronavirus S genes accumulated about 3-fold less (p < 0.001) non-synonymous mutations (dN) over time than IAV HA genes. In both IAV and HCoV, the average rate of dN within the receptor binding domains (RBD) was about 5-fold higher (p < 0.0001) than in other glycoprotein regions. Similarly, most sites showing evidence for positive selection occurred within the RBD (HCoV-229E, 6/14 sites, p < 0.05; HCoV-OC43, 23/38 sites, p < 0.01; IAV, 13/15 sites, p = 0.08). In sum, the evolutionary dynamics of HCoV and IAV showed several similarities, yet amino acid changes potentially representing antigenic drift occurred on a lower scale in endemic HCoV compared to IAV H3N2. It seems likely that pandemic SARS-CoV-2 evolution will bear similarities with IAV evolution including accumulation of adaptive changes in the RBD, requiring vaccines to be updated regularly, whereas higher SARS-CoV-2 evolutionary stability resembling endemic HCoV can be expected in the post-pandemic stage.

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Section: Resultsmentioning

confidence: 99%

The evolutionary dynamics of endemic human coronaviruses

Drosten

Drexler

2021

Virus Evolution

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“…HDV stock solved in 20 µl HGM per well was added for infection and cells were incubated for 6 h with final concentration of 700 genome equivalents/cell of HDV particles. HDV production was done in vitro as described before 55 , 56 . RT-qPCR was performed to determine genome equivalents.…”

Section: Methodsmentioning

confidence: 99%

Selective hepatitis B and D virus entry inhibitors from the group of pentacyclic lupane-type betulin-derived triterpenoids

Kirstgen

Lowjaga

Müller

et al. 2020

Sci Rep

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Current treatment options against hepatitis B and D virus (HBV/HDV) infections have only limited curative effects. Identification of Na+/taurocholate co-transporting polypeptide (NTCP) as the high-affinity hepatic receptor for both viruses in 2012 enables target-based development of HBV/HDV cell-entry inhibitors. Many studies already identified appropriate NTCP inhibitors. However, most of them interfere with NTCP’s physiological function as a hepatic bile acid transporter. To overcome this drawback, the present study aimed to find compounds that specifically block HBV/HDV binding to NTCP without affecting its transporter function. A novel assay was conceptualized to screen for both in parallel; virus binding to NTCP (measured via binding of a preS1-derived peptide of the large HBV/HDV envelope protein) and bile acid transport via NTCP. Hits were subsequently validated by in vitro HDV infection studies using NTCP-HepG2 cells. Derivatives of the birch-derived pentacyclic lupane-type triterpenoid betulin revealed clear NTCP inhibitory potency and selectivity for the virus receptor function of NTCP. Best performing compounds in both aspects were 2, 6, 19, and 25. In conclusion, betulin derivatives show clear structure–activity relationships for potent and selective inhibition of the HBV/HDV virus receptor function of NTCP without tackling its physiological bile acid transport function and therefore are promising drug candidates.

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“…HDV production was done in vitro as described before [ 20 , 21 ]. RT-qPCR was performed to determine genome equivalents.…”

Section: Methodsmentioning

confidence: 99%

Hepatitis D Virus Entry Inhibitors Based on Repurposing Intestinal Bile Acid Reabsorption Inhibitors

Kirstgen

Lowjaga

Müller

et al. 2021

Viruses

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Identification of Na+/taurocholate co-transporting polypeptide (NTCP) as high-affinity hepatic entry receptor for the Hepatitis B and D viruses (HBV/HDV) opened the field for target-based development of cell-entry inhibitors. However, most of the HBV/HDV entry inhibitors identified so far also interfere with the physiological bile acid transporter function of NTCP. The present study aimed to identify more virus-selective inhibitors of NTCP by screening of 87 propanolamine derivatives from the former development of intestinal bile acid reabsorption inhibitors (BARIs), which interact with the NTCP-homologous intestinal apical sodium-dependent bile acid transporter (ASBT). In NTCP-HEK293 cells, the ability of these compounds to block the HBV/HDV-derived preS1-peptide binding to NTCP (virus receptor function) as well as the taurocholic acid transport via NTCP (bile acid transporter function) were analyzed in parallel. Hits were subsequently validated by performing in vitro HDV infection experiments in NTCP-HepG2 cells. The most potent compounds S985852, A000295231, and S973509 showed in vitro anti-HDV activities with IC50 values of 15, 40, and 70 µM, respectively, while the taurocholic acid uptake inhibition occurred at much higher IC50 values of 24, 780, and 490 µM, respectively. In conclusion, repurposing of compounds from the BARI class as novel HBV/HDV entry inhibitors seems possible and even enables certain virus selectivity based on structure-activity relationships.

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Highly diversified shrew hepatitis B viruses corroborate ancient origins and divergent infection patterns of mammalian hepadnaviruses

Cited by 19 publications

References 41 publications

The evolutionary dynamics of endemic human coronaviruses

The evolutionary dynamics of endemic human coronaviruses

Selective hepatitis B and D virus entry inhibitors from the group of pentacyclic lupane-type betulin-derived triterpenoids

Hepatitis D Virus Entry Inhibitors Based on Repurposing Intestinal Bile Acid Reabsorption Inhibitors

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