Evolution of hepatitis C virus non-structural 5A gene in the progression of liver disease to hepatocellular carcinoma.
BACKGROUND
The interaction between the hepatitis C virus (HCV) non-structural 5A (NS5A) protein of HCV and the protein kinase R (PKR), which is an effector of the cellular antiviral response and has been defined as a tumour suppressor, may affect the control of protein synthesis and cell growth.


OBJECTIVE
We investigated the genetic evolution of the NS5A region in the NS5A PKR-binding domain (NS5A-PKRbd) of patients with HCV 1b-related cirrhosis who subsequently developed or not hepatocellular carcinoma (HCC).


METHODS
The quasispecies composition of NS5A-PKRbd was inferred by sequencing an average of 15 clones per sample in specimens obtained from 26 patients with cirrhosis who developed or not HCC during a follow-up of 5 years.


RESULTS
At baseline, 13/17 patients with final HCC and six out of nine patients with cirrhosis who subsequently did not develop HCC harboured a wild-type (wt) strain master sequence. Over time, the prevalence of wt strain was higher in patients who developed HCC with respect to those who maintained the cirrhosis status (15/17 vs 4/9, respectively; P=0.0166).


CONCLUSIONS
The maintenance of or evolution to the wt strain of the NS5A domain in cirrhotic patients with final HCC highlights the central role of NS5A protein in the viral life cycle and in the progression of liver disease.
De Mitri
Maria Stella
MS
Department of Internal Medicine, Cardioangiology, Hepatology, University of Bologna, Bologna, Italy. sdemitri@med.unibo.it
Cassini
Romina
R
Bagaglio
Sabrina
S
Morsica
Giulia
G
Andreone
Pietro
P
Marino
Nicoletta
N
Bernardi
Mauro
M
D000368:Aged; D000595:Amino Acid Sequence; D006528:Carcinoma, Hepatocellular / Q000201:enzymology / Q000821:virology*; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D004252:DNA Mutational Analysis; D004279:DNA, Viral / Q000032:analysis; D018450:Disease Progression; D005260:Female; D005500:Follow-Up Studies; D016174:Hepacivirus / Q000235:genetics*; D006526:Hepatitis C / Q000150:complications* / Q000201:enzymology / Q000235:genetics; D006801:Humans; D008103:Liver Cirrhosis / Q000150:complications* / Q000201:enzymology / Q000821:virology; D008113:Liver Neoplasms / Q000201:enzymology / Q000821:virology*; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D009154:Mutation; D012367:RNA, Viral / Q000097:blood; D020539:Sequence Analysis, Protein; D017361:Viral Nonstructural Proteins / Q000235:genetics* / Q000378:metabolism; D019892:eIF-2 Kinase / Q000378:metabolism; D012324:RNA-Dependent RNA Polymerase
D004279:DNA, Viral; D012367:RNA, Viral; D017361:Viral Nonstructural Proteins; D019892:eIF-2 Kinase; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase