Strong Replication Interference Between Hepatitis Delta Viruses in Human Liver Chimeric Mice
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Strong Replication Interference Between Hepatitis Delta Viruses in Human Liver Chimeric Mice. / Giersch, Katja; Hermanussen, Lennart; Volz, Tassilo; Volmari, Annika; Allweiss, Lena; Sureau, Camille; Casey, John; Huang, Jiabin; Fischer, Nicole; Lütgehetmann, Marc; Dandri, Maura.
In: FRONT MICROBIOL, Vol. 12, 2021, p. 671466.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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TY - JOUR
T1 - Strong Replication Interference Between Hepatitis Delta Viruses in Human Liver Chimeric Mice
AU - Giersch, Katja
AU - Hermanussen, Lennart
AU - Volz, Tassilo
AU - Volmari, Annika
AU - Allweiss, Lena
AU - Sureau, Camille
AU - Casey, John
AU - Huang, Jiabin
AU - Fischer, Nicole
AU - Lütgehetmann, Marc
AU - Dandri, Maura
N1 - Copyright © 2021 Giersch, Hermanussen, Volz, Volmari, Allweiss, Sureau, Casey, Huang, Fischer, Lütgehetmann and Dandri.
PY - 2021
Y1 - 2021
N2 - Background: Hepatitis D Virus (HDV) is classified into eight genotypes with distinct clinical outcomes. Despite the maintenance of highly conserved functional motifs, it is unknown whether sequence divergence between genotypes, such as HDV-1 and HDV-3, or viral interference mechanisms may affect co-infection in the same host and cell, thus hindering the development of HDV inter-genotypic recombinants. We aimed to investigate virological differences of HDV-1 and HDV-3 and assessed their capacity to infect and replicate within the same liver and human hepatocyte in vivo.Methods: Human liver chimeric mice were infected with hepatitis B virus (HBV) and with one of the two HDV genotypes or with HDV-1 and HDV-3 simultaneously. In a second set of experiments, HBV-infected mice were first infected with HDV-1 and after 9 weeks with HDV-3, or vice versa. Also two distinct HDV-1 strains were used to infect mice simultaneously and sequentially. Virological parameters were determined by strain-specific qRT-PCR, RNA in situ hybridization and immunofluorescence staining.Results: HBV/HDV co-infection studies indicated faster spreading kinetics and higher intrahepatic levels of HDV-3 compared to HDV-1. In mice that simultaneously received both HDV strains, HDV-3 became the dominant genotype. Interestingly, antigenomic HDV-1 and HDV-3 RNA were detected within the same liver but hardly within the same cell. Surprisingly, sequential super-infection experiments revealed a clear dominance of the HDV strain that was inoculated first, indicating that HDV-infected cells may acquire resistance to super-infection.Conclusion: Infection with two largely divergent HDV genotypes could be established in the same liver, but rarely within the same hepatocyte. Sequential super-infection with distinct HDV genotypes and even with two HDV-1 isolates was strongly impaired, suggesting that virus interference mechanisms hamper productive replication in the same cell and hence recombination events even in a system lacking adaptive immune responses.
AB - Background: Hepatitis D Virus (HDV) is classified into eight genotypes with distinct clinical outcomes. Despite the maintenance of highly conserved functional motifs, it is unknown whether sequence divergence between genotypes, such as HDV-1 and HDV-3, or viral interference mechanisms may affect co-infection in the same host and cell, thus hindering the development of HDV inter-genotypic recombinants. We aimed to investigate virological differences of HDV-1 and HDV-3 and assessed their capacity to infect and replicate within the same liver and human hepatocyte in vivo.Methods: Human liver chimeric mice were infected with hepatitis B virus (HBV) and with one of the two HDV genotypes or with HDV-1 and HDV-3 simultaneously. In a second set of experiments, HBV-infected mice were first infected with HDV-1 and after 9 weeks with HDV-3, or vice versa. Also two distinct HDV-1 strains were used to infect mice simultaneously and sequentially. Virological parameters were determined by strain-specific qRT-PCR, RNA in situ hybridization and immunofluorescence staining.Results: HBV/HDV co-infection studies indicated faster spreading kinetics and higher intrahepatic levels of HDV-3 compared to HDV-1. In mice that simultaneously received both HDV strains, HDV-3 became the dominant genotype. Interestingly, antigenomic HDV-1 and HDV-3 RNA were detected within the same liver but hardly within the same cell. Surprisingly, sequential super-infection experiments revealed a clear dominance of the HDV strain that was inoculated first, indicating that HDV-infected cells may acquire resistance to super-infection.Conclusion: Infection with two largely divergent HDV genotypes could be established in the same liver, but rarely within the same hepatocyte. Sequential super-infection with distinct HDV genotypes and even with two HDV-1 isolates was strongly impaired, suggesting that virus interference mechanisms hamper productive replication in the same cell and hence recombination events even in a system lacking adaptive immune responses.
U2 - 10.3389/fmicb.2021.671466
DO - 10.3389/fmicb.2021.671466
M3 - SCORING: Journal article
C2 - 34305837
VL - 12
SP - 671466
JO - FRONT MICROBIOL
JF - FRONT MICROBIOL
SN - 1664-302X
ER -