Epatite Cronica B

Il Virus

Giovanni Raimondo

U.O.C. EpatologiaClinica e Biomolecolare

A.O.U. Policlinico G. Martino Messina

Giovanni Raimondo

HBV: Il Virus

Il sottoscritto dichiara di non aver avuto negli ultimi 12 mesi conflitto d’interesse in relazione a questa presentazione

e

che la presentazione non contiene discussione di farmaci in studio o ad uso off-label

HBV GENOME

S gene: pre S1(large S), preS2 (middle S), S (small S)

X gene: X

Core gene: core, e

Pol gene: P

H

E

P

A

T

I

T

I

S

B V

I

R

U

S

H

E

P

A

T

I

T

I

S

B V

I

R

U

S

nucleus citoplasm

repair

mRNA transcription

Core particle plus strand syntesis

mRNA transport

translationRibosome

Transport to cell membrane

HBV

preCore

HBXSecreted HBeAg

ER

Spheres and Filamentes containing HBsAg

Small HBsMedium HBsLarge HBs

Envelope

Subgenomic and Geneomic RNA

Pre-genomic RNACorePol

cccDNA

Golgi complex

Entry of HBV into cell and uncoating

Core particle minus strand syntesis

Core assembly and RNA packaging

HBV life cycle

RECYCLING

Visualization of HBV integration breakpoints in the HCC and HBV genomes.

HEPATITIS B VIRUS Genome Organization

• 3.2 kb pdDNA• 3 promoters = Core, S-, and X• 4 ORF = preC/Core, pre-S1/pre-

S2/S, Polymerase, X-gene

HBV open reading frames

* aa 108/119

according to genotype

*

modified from Warner and Locarnini

Modified from Chan H L-Y et al, J Hepatol 2011

HBVwt HBV172* HBVwt + HBV172* mix

Warner, N and Locarnini, S. Hepatology 2008.

preS1 mutant HBV Wild type HBV

Pollicino et al, Hepatology 2012

Cancer Sci. 2006 Aug;97(8):683-8.

Distribution of preS2-defective variants in

HBsAg+ patients (pts)¶ with difefrent clinical pictures

Raimondo et al, J hepatol 2004

Diagnosis

Inactive Carriers°

Chronic hepatitis°*

Cirrhosis°*

HCC°*

N° pts

15

50

26

19

N° pS2 variants

2

25

13

16

°p=0.002

*p=0.02

¶ All pts infected with genotype D

Prevalence of pre-S mutants in patients infected with genotype

B, C, or mixed genotypesChen F-B et al, Gastroenterology 2006

cc : chronic (inactive) carriers

CH : chronic hepatitis

LC : liver cirrhosis

Deletion

Wild-type + deletion

Wild-type

The two separate pathways of HBsAg and HBVDNA production

Nguyen T, J Hepatol 2010

HBsAg secretory pathway and the viral replication pathway

are distinct within the hepatocyte

Geographic Distributionof HBV Genotypes

Genotype A : World-wide

“ “ B : Asia

“ “ C : Asia

“ “ D : South Europe, Americas, Australia

“ “ E : Africa

“ “ F : Native Americans and Polynesians

“ “ G : Europe, U.S.A.

“ “ H : Native Americans

Chimpanzee

Gibbon

Orang-Utan

Woolly monkey

T--C--

--T

CC-

-C--A-

--A-G-

ATG

1839

Insertion

Deletion

DR1 RNA encapsidation signal

X gene

TAA TAG

1817CAA

1874 1896 1897

AAG TGG

TAG

1838/9

pre-C ATG C ATG

B

A

TGA

pre-C pregenome/C mRNA

1899/1900

pre-C region/precore protein

1814-6

Pre-C mutations preventing HBeAg synthesis

Pre-C C P

X1374 1836

1591 1850Enhancer II/core promoter region

1762A T

1764G A

Core Promoter Mutations

Saint Jerome

Antonello da Messina

London, National Gallery