A dominant hepatitis B virus population defective in virus secretion because of several S-gene mutations from a patient with fulminant hepatitis

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August 2001 . Volume 34 . Number 2

Original Articles

A dominant hepatitis B virus population defective in virus secretion because

of several S-gene mutations from a patient with fulminant hepatitis

Tatyana Kalinina1,3 [MEDLINE LOOKUP]

Riu1 [MEDLINE LOOKUP]

Lutz Fischer1,2 [MEDLINE LOOKUP]

Hans Will1 [MEDLINE LOOKUP]

a Sterneck1,2 [MEDLINE LOOKUP]

ABSTRACT:

There is increasing evidence that certain pathogenic hepatitis B virus

(HBV) variants may play a role in the pathogenesis of fulminant hepatitis

(FHB). Recently, we isolated from a patient with fulminant recurrent

hepatitis B after liver transplantation variants with enhanced replication

competence and a possible defect in viral particle secretion. Both viral

features may have contributed to the severity of the disease. The aim of

this study was to prove the secretion defect of these variants, to analyze

the consequences, and to identify the responsible viral mutations. The

variant genomes and appropriate wild-type/variant hybrid genomes were

functionally characterized after transfection in human hepatoma cells. Two

cloned genomes and the polymerase chain reaction (PCR)-amplified mixture of

full-length genomes showed a block in viral particle secretion. This was

caused by a combination of amino acid changes in the S-protein including the

mutation G145R frequently emerging after hyperimmunoglobulin treatment. The

mutations induced retention of the surface proteins in an endoplasmic

reticulum (ER)-like compartment, but no intracellular accumulation. These

data provide evidence for the in vivo existence of a dominant HBV population

with a severe defect in viral particle secretion caused by mutations in the

S-gene. This viral phenotype in combination with the enhanced replication

competence may have contributed to the fulminant clinical course of the

infection. (HEPATOLOGY 2001;34:385-394.)

a.. From the 1Heinrich-Pette-Institut für experimentelle Virologie und

Immunologie an der Universität Hamburg; 2Universitätskrankenhaus Eppendorf,

Hamburg, Germany; and the 3Institute of Virology, Moscow, Russia.

b.. Received January 26, 2001.

c.. Accepted May 16, 2001.

d.. Supported by the " Bundesministerium für Forschung und Technik " (BMFT;

NO. 01KI9558) and the " Deutsche Forschungsgemeinschaft " (DFG; STE 970/1-2).

e.. Address reprint requests to: a Sterneck, M.D.,

Universitätskrankenhaus Eppendorf, istrasse 52, 20246 Hamburg,

Germany. Fax: (49) 40-42803-6861; E-mail: sterneck@... .

f.. ______________________________