Evolution of hepatitis C viral quasispecies and hepatic injury in perinatally infected children followed prospectively

doi:10.1073/pnas.0602546103

Evolution of hepatitis C viral quasispecies and hepatic injury in perinatally infected children followed prospectively

Departments of *Medical Sciences and
^‡‡Cytomorphology, University of Cagliari, SS 554 Bivio Sestu, 09042 Cagliari, Italy;
^‡Department of Clinical Medicine, University of Rome “La Sapienza,” Viale Regina Elena 324, 00185 Rome, Italy;
^§Department of Transfusion Medicine, Warren G. Magnuson Clinical Center, National Institutes of Health, 10 Center Drive, Bethesda, MD 20892;
^¶Department of Pediatrics, University of Turin, Piazza Polonia 94, 10126 Turin, Italy;
^‖Department of Gynecological Sciences and Perinatology, University of Rome “La Sapienza,” Via dei Sardi 58, 00185 Rome, Italy;
**Institute of Neonatology, University of Cagliari, Via Ospedale 119, 09124 Cagliari, Italy; and
^††Department of Pediatrics, University Federico II, Via Pansini 5, 80131 Naples, Italy

Contributed by Harvey J. Alter, March 30, 2006

Abstract

Perinatal infection with hepatitis C virus (HCV) is characterized by a wide range of alanine aminotransferase (ALT) levels. The mechanisms responsible for this variability are unknown. We examined whether the evolution of the HCV quasispecies was associated with different ALT profiles in perinatally infected children. Sequences within HCV envelope 1 and 2 genes, inclusive of the hypervariable region 1, the viral load, and the nascent humoral immunity were analyzed in serial serum samples from 12 perinatally infected children prospectively followed for a median of 53 months. These patients were selected to represent two different ALT patterns during the first year of life: 6 had high levels (maximum values ranging from 4.2 to 30 times the normal upper limit), and 6 had normal or slightly elevated levels (<2 times the normal upper limit). Two patterns of viral evolution were identified according to the ALT profiles. Biochemical evidence of hepatic injury was invariably associated with a mono- or oligoclonal viral population, whereas mild or no liver damage correlated with the early emergence of a heterogeneous viral quasispecies. Consistent with selective immune pressure, amino acid changes occurred almost exclusively within the hypervariable region 1 and were temporally associated with antibody seroconversion; at this time, the difference in genetic diversity between the two groups was highly significant (P = 0.002). The two patterns of viral evolution persisted over time and did not correlate with viral load or genotype. Our study demonstrates that, in perinatally infected children, the evolution of HCV quasispecies correlates with hepatic injury.

Footnotes

^†To whom correspondence should be addressed. E-mail: farcip{at}pacs.unica.it
Author contributions: P.F. and I.Q. designed research; P.F., S.F., R.S., A.C., and D.C. performed research; G.D. contributed new reagents/analytic tools; P.F., I.Q., H.J.A., E.P., A.M.C., R.L., R.I., and A.V. analyzed data; and P.F. and P.-A.T. wrote the paper.
Conflict of interest statement: No conflicts declared.
Data deposition: The sequences reported in this paper have been deposited in the GenBank database (accession nos. DQ504441–DQ507112).
Abbreviations:

Abbreviations:

ALT,

alanine aminotransferase;

E,

envelope glycoprotein;

HCV,

hepatitis C virus;

HVR1,

hypervariable region 1.