Molecular Determinants of Mouse Adaptation of Rat Hepacivirus

Wolfisberg, Raphael; Holmbeck, Kenn; Billerbeck, Eva; Thorselius, Caroline E; Batista, M.; Fahnøe, Ulrik; Lundsgaard, Emma A; Kennedy, Matthew J.; Nielsen, Louise; Rice, Charles M.; Bukh, Jens; Scheel, Troels K. H.

doi:10.1128/jvi.01812-22

Cited by 2 publications

(8 citation statements)

References 39 publications

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“…We infected 10 different CC mouse strains with a mixture of 2 sub-populations of mouse-derived NrHV inoculum, NrHV-A and -B along with the mouse-adapted NrHV-B SLIS at a ratio of 1:1:1 (A:B:B SLIS ) (Supplemental Figure S1, http://links.lww.com/HEP/H952 ). 13 We utilized this mixture to give the best possible foundation for persistency, not knowing which variant would be optimal in the CC. After infection, we monitored viremia for 4 weeks which is 1–2 weeks after WT C57BL/6J [wild-type (WT)] mice typically clear.…”

Section: Resultsmentioning

confidence: 99%

“…In all 3 CC mouse strains, the mouse-adapted NrHV-B SLIS variant was rapidly selected for, likely due to its mutations T190S, V353L, F369I, and N550S, which adapt the virus to WT B6 mice. 12 , 13 Several mutations residing in an MHC-I epitope conserved between mice and rats (T184A, S191F, V196A) were observed in viral genomes from all CC strains. 26 In addition, either A698V or C715S appeared to be selected in p7 but rarely together.…”

Section: Resultsmentioning

confidence: 99%

“…DNA from consensus clones NrHV-A, NrHV-B, and the mouse-adapted NrHV-B SLIS , carrying the T190S, V353L, F369I, and N550S mutations, 13 were linearized using MIuI and purified using DNAclean and concentrator (Zymo). RNA was transcribed from 1 ug of MIuI -linearized DNA using T7 RiboMAX Express Large Scale RNA Production System (Promega).…”

Section: Methodsmentioning

confidence: 99%

“…Analysis was performed as described. 11 , 13 In short, pair-end reads were trimmed and filtered by Sickle and subsequently mapped by BWA onto the NrHV-B reference (GenBank: ON758386) using the MEM algorithm. Samtools were used to process the alignment files, and Lofreq was applied to call SNPs that were translated by SNPEffect.…”

Section: Methodsmentioning

confidence: 99%

“…NrHV mouse adaptation delays clearance until after 3–5 weeks, whereas transient depletion of CD4 T-cells before infection leads to persistent infection. 12 , 13 Models of chronic hepacivirus infection in fully immune-competent mice without immune manipulation are not yet available.…”

Section: Introductionmentioning

confidence: 99%

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Host genetic variation guides hepacivirus clearance, chronicity, and liver fibrosis in mice

et al. 2023

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Background & Aims: Human genetic variation is thought to guide the outcome of hepatitis C virus (HCV) infection but model systems within which to dissect these host genetic mechanisms are limited. Norway rat hepacivirus (NrHV), closely related to HCV, causes chronic liver infection in rats but causes acute self-limiting hepatitis in typical strains of laboratory mice, which resolves in two weeks. The Collaborative Cross (CC) is a robust mouse genetics resource comprised of a panel of recombinant inbred strains, which model the complexity of the human genome and provide a system within which to understand diseases driven by complex allelic variation. Approach & Results: We infected a panel of CC strains with NrHV and identified several that failed to clear virus after 4 weeks. Strains displayed an array of virologic phenotypes ranging from delayed clearance (CC046) to chronicity (CC071, CC080) with viremia for at least 10 months. Body weight loss, hepatocyte infection frequency, viral evolution, T-cell recruitment to the liver, liver inflammation and the capacity to develop liver fibrosis varied among infected CC strains. Conclusions: These models recapitulate many aspects of HCV infection in humans and demonstrate that host genetic variation affects a multitude of virus and host phenotypes. These models can be used to better understand the molecular mechanisms that drive hepacivirus clearance and chronicity, the virus and host interactions that promote chronic disease manifestations like liver fibrosis, therapeutic and vaccine performance, and how these factors are affected by host genetic variation.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Host genetic variation guides hepacivirus clearance, chronicity, and liver fibrosis in mice

et al. 2023

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Phenotype and fate of liver-resident CD8 T cells during acute and chronic hepacivirus infection

Dravid,

Murthy,

Attia

et al. 2023

PLoS Pathog

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Immune correlates of hepatitis C virus (HCV) clearance and control remain poorly defined due to the lack of an informative animal model. We recently described acute and chronic rodent HCV-like virus (RHV) infections in lab mice. Here, we developed MHC class I and class II tetramers to characterize the serial changes in RHV-specific CD8 and CD4 T cells during acute and chronic infection in C57BL/6J mice. RHV infection induced rapid expansion of T cells targeting viral structural and nonstructural proteins. After virus clearance, the virus-specific T cells transitioned from effectors to long-lived liver-resident memory T cells (TRM). The effector and memory CD8 and CD4 T cells primarily produced Th1 cytokines, IFN-γ, TNF-α, and IL2, upon ex vivo antigen stimulation, and their phenotype and transcriptome differed significantly between the liver and spleen. Rapid clearance of RHV reinfection coincided with the proliferation of virus-specific CD8 TRM cells in the liver. Chronic RHV infection was associated with the exhaustion of CD8 T cells (Tex) and the development of severe liver diseases. Interestingly, the virus-specific CD8 Tex cells continued proliferation in the liver despite the persistent high-titer viremia and retained partial antiviral functions, as evident from their ability to degranulate and produce IFN-γ upon ex vivo antigen stimulation. Thus, RHV infection in mice provides a unique model to study the function and fate of liver-resident T cells during acute and chronic hepatotropic infection.

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Molecular Determinants of Mouse Adaptation of Rat Hepacivirus

Cited by 2 publications

References 39 publications

Host genetic variation guides hepacivirus clearance, chronicity, and liver fibrosis in mice

Host genetic variation guides hepacivirus clearance, chronicity, and liver fibrosis in mice

Phenotype and fate of liver-resident CD8 T cells during acute and chronic hepacivirus infection

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