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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

The mechanism of HCV extrahepatic infection

Michael M.C. Lai

Institute of Molecular Biology

Academia Sinica

Sept. 21, 2012 at Wuhan



Evidence that pbmc infection by hcv is causally linked to b cell lymphoma
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)


A lymphotropic HCV (HCV-SB) isolated from a B-cell lymphoma 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


Candidate hcv receptors
Candidate HCV receptors cell lymphoma

  • 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)


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


Molecular mechanism of viral lympho- vs hepatotropism virus replication and intracellular lipids.

T7 in vitro

transcripts

Electroporation

into Huh7.5 and Raji

Detection (qRT-PCR)

Harvest

Cloned cDNA


SB virus RNA, but not JFH-1 Virus, Replicates in Raji Cells virus replication and intracellular lipids.

m

m

Raji


Jfh 1 virus but not sb virus rna replicates in huh7 5 cells
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.


Chimera Virus containing E1-E2 of SB Strain Produces CellsHigh Levels of HCV RNA in Raji Cells

150000


Infection of Cellstarget 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


Infectivity of HCV Pseudo-particles is Determined Cells

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



Consequences of hcv infection of b cells
Consequences of HCV infection of B cells 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


iNOS Cells

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


Higher mutation frequency in oncogenes in hcv associated b cell lymphoma and hcc
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)



Extrahepatic infection particularly pbmc infection plays an important role in hcv pathogenesis
Extrahepatic infection, particularly PBMC infection, plays an important role in HCV pathogenesis


Acknowledgment
Acknowledgment an important role in HCV pathogenesis

  • Keigo Machida

    • University of Southern California

  • Chao Kuen Lai

  • King-Song Jeng

    • Academia Sinica, taiwan


Thanks for your attention

Thanks for your attention. an important role in HCV pathogenesis


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