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The mechanism of HCV extrahepatic infection

The mechanism of HCV extrahepatic infection. Michael M.C. Lai Institute of Molecular Biology Academia Sinica. Sept. 21, 2012 at Wuhan. Clinical manifestations of HCV. Evidence that PBMC infection by HCV is causally linked to B cell lymphoma.

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The mechanism of HCV extrahepatic infection

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  1. The mechanism of HCV extrahepatic infection Michael M.C. Lai Institute of Molecular Biology Academia Sinica Sept. 21, 2012 at Wuhan

  2. Clinical manifestations of HCV

  3. Evidence that PBMC infection by HCV is causally linked to B cell lymphoma • High frequency of HCV infection (20-40%) among B-cell lymphoma patients in some geographical regions • HCV-transgenic mice develop B-cell lymphoma (Kasama et al. 2011) • Antiviral therapy (interferon plus ribavirin) of HCV(+) lymphoma patients can induce tumor remission (Hermine et al., 2002: Levine et al., 2003) • A lymphotropic HCV (SB virus) was isolated from a B-cell lymphoma (Sung et al., 2003)

  4. A lymphotropic HCV (HCV-SB) isolated from a B-cell lymphoma • Isolated from the spleen of an HCV-positive patient with B-cell lymphoma and mixed cryoglobulinemia • HCV-SB virus particles can infect B cells and T cells but not hepatocytes. • HCV-SB has typical characteristics of hepatotropic HCV strains

  5. Candidate HCV receptors • CD81 • ubiquitous, initial virus binding • SR-B1 (scavenger receptor B1) • Hepatocyte, dendritic cells • LDLR • ubiquitous • L-SIGN, DC-SIGN • LSEC, Kupffer cells • Glycosaminoglycans (heparan sulfate) • Claudin-1, Occludin (entry molecules) • tight junction molecules (liver, epithelial cells)

  6. Hecker, E. & Ott, M. 2011. Ubique ties between hepatitis C virus replication and intracellular lipids. Cell. 22(6).243

  7. Molecular mechanism of viral lympho- vs hepatotropism T7 in vitro transcripts Electroporation into Huh7.5 and Raji Detection (qRT-PCR) Harvest Cloned cDNA

  8. SB virus RNA, but not JFH-1 Virus, Replicates in Raji Cells m m Raji

  9. JFH-1 Virus, but not SB Virus RNA, Replicates in Huh7.5 Cells m m Huh7.5 • SB virus is lymphotropic. JFH1 virus is hepatotropic.

  10. Chimera Virus containing E1-E2 of SB Strain Produces High Levels of HCV RNA in Raji Cells 150000

  11. Infection of target cells GFP orluciferase expression HCVpp entry Rajior Huh7.5 Study virus entry, receptors, host range, etc. HCV Pseudoparticle System (HCVpp) A retrovirus reporter virus with HCV envelope proteins HCVE1/E2 gag-pol (retrovirus) y GFP or Luciferase

  12. Infectivity of HCV Pseudo-particles is Determined by E1-E2 of SB Strain in Raji Cells FACS for GFP reporter with HCVpp at 72 h p.i Normalized for p24 HIV core antigen Raji 1/100 1/100 Huh7.5

  13. Anti-CD81 and IFN Treatment Inhibit HCV Replication

  14. Consequences of HCV infection of B cells • Inhibition of DNA damage repair: chromosomal translocation • Uncoupling of mitotic checkpoint: chromosomal polyploidy • Induction of error-prone DNA polymerases: hypermutation of immunoglobulin and protooncogenes

  15. iNOS inhibitor 1400W Mutation frequency X10-4 HCV infection % clones mutated Locus p53 - + + - - + 0 (0/18) 15 (3/20) 0 (0/20) 0 7.25 0 VH - + + - - + 15 (3/20) 55 (11/20) 35 (7/20) 4.1 20.3 9.6 Mutation frequencies of p53 and VH in HCV-infected human B cell lines

  16. Higher mutation frequency in oncogenes in HCV-associated B cell lymphoma and HCC Mutation frequency (mutation/bp) x10-4 p53 -catenin HCV-associated Non-HCV HCV tumor nontumor HBV tumor nontumor Nonviral tissues 30 3.9 35 5.9 3.9 0 2.5 33 0 30 11 7.4 7.4 4.4 B cell lymphomas Hepatocellular carcinomas (HCC)

  17. HCV-SB also infects T cells and suppresses interferon signaling

  18. Extrahepatic infection, particularly PBMC infection, plays an important role in HCV pathogenesis

  19. Acknowledgment • Keigo Machida • University of Southern California • Chao Kuen Lai • King-Song Jeng • Academia Sinica, taiwan

  20. Thanks for your attention.

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