Evolution of hepatitis C viral quasispecies and hepatic injury in perinatally infected children followed prospectively - PubMed (original) (raw)

. 2006 May 30;103(22):8475-80.

doi: 10.1073/pnas.0602546103. Epub 2006 May 17.

Isabella Quinti, Stefania Farci, Harvey J Alter, Rita Strazzera, Elvia Palomba, Alessandra Coiana, Daniele Cao, Anna Maria Casadei, Ritarella Ledda, Raffaele Iorio, Angela Vegnente, Giacomo Diaz, Pier-Angelo Tovo

Affiliations

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

Patrizia Farci et al. Proc Natl Acad Sci U S A. 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. The sequences reported in this paper have been deposited in the GenBank database (accession nos. DQ 504441-DQ 507112).

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Conflict of interest statement

Conflict of interest statement: No conflicts declared.

Figures

Fig. 1.

Fig. 1.

Mean ALT values and serum HCV RNA during long-term follow-up in perinatally infected children with high (A) and low (B) ALT levels. Bars indicate the geometric mean ± SE of ALT values and the mean ± SE of serum HCV RNA (measured on a log10 scale), calculated from the means of each patient. Mean values for each patient were calculated from all available values per year. The number of patients analyzed is shown inside the bars. The difference in the mean ALT levels between the two groups of patients was statistically significant during the first (P = 0.002) and second (P = 0.004) years of life.

Fig. 2.

Fig. 2.

Genetic diversity (distance among variants) and number of quasispecies variants within and outside HVR1 in perinatally infected children with high and low ALT levels. (A and C) Genetic diversity within the viral quasispecies, as measured by mean Hamming distance both within and outside HVR1. (B and D) Number of quasispecies variants. The values indicate the number of variants per 27 amino acids both within and outside HVR1. The data represent the mean ± SE of the results obtained from all of the patients within each group at different time points. In patients with high ALT levels, “Pre-seroconversion” denotes the results obtained after a mean ± SE of 4.6 ± 1.7 months; “Post-seroconversion” denotes the results obtained after a mean ± SE of 12.8 ± 2.0 months; “Late-follow-up” denotes the results obtained after a mean ± SE of 54.2 ± 5.5 months. In patients with low ALT levels, “Pre-seroconversion” denotes the results obtained after a mean ± SE of 3.6 ± 1.1 months; “Post-seroconversion” denotes the results obtained after a mean ± SE of 13.8 ± 2.3 months; “Late-follow-up” denotes the results obtained after a mean ± SE of 53.5 ± 1.2 months. The analysis before seroconversion was performed on 10 patients because, for 2 (1 in each group), insufficient serum was available; after antibody seroconversion, the analysis was extended to all 12 patients; at the late time point, the analysis was performed on the 8 patients (4 in each group) for whom a long-term follow-up was available.

Fig. 3.

Fig. 3.

Clinical course and evolution of the HCV quasispecies during the first 2 years of perinatally acquired HCV infection in four representative children, two with high ALT levels (Patients 1 and 2) and two with normal or low ALT levels (Patients 7 and 8). Patient numbers are the same as in Table 1. (A, C, E, and G) Clinical course of hepatitis C. The light blue areas denote ALT levels. The red horizontal bars denote positive assays for serum HCV RNA by PCR. The red lines denote the titer of serum HCV RNA on a logarithmic scale. The yellow horizontal bars denote the infant’s nascent antibody response to HCV, as detected by third generation RIBA. (B, D, F, and H) Number of viral variants and genetic diversity (genetic distance among variants) of the HCV quasispecies within the 27 amino acids of the HVR1. The vertical bars indicate the number and the proportion of viral variants within each sample. The dominant viral variant found in each patient at the first time point is indicated in blue; other variants are indicated by additional colors. Within the vertical bars, each variant is identified by a different color. The same color indicates identity between viral variants detected at different time points within each patient and not between different patients. The viral population diversity (black line) was calculated by mean Hamming distance from the predicted amino acid sequences obtained from each sample.

Fig. 4.

Fig. 4.

Long-term clinical course and evolution of the HCV quasispecies during long-term follow-up of perinatally acquired HCV infection in three representative children, two with high ALT levels (Patients 1 and 6), one of whom had an unusually severe hepatitis, with an ALT peak of 1,213 IU/liter (Patient 6), and one with low ALT levels (Patient 8). Patient numbers are the same as in Table 1. (A, C, and E) Long-term clinical course of hepatitis C. (B, D, and F) Long-term evolution of the HCV quasispecies. The symbols are the same as in the legend to Fig. 3.

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