Dominant role of host selective pressure in driving hepatitis C virus evolution in perinatal infection

The dynamics of the genetic diversification of hepatitis C virus (HCV) popu lations was addressed in perinatal infection. Clonal sequences of hypervari able region 1 of the putative E2 envelope protein of HCV were obtained from four HCV-infected newborns (sequential samples spanning a period of 6 to 1 3 months after birth) and from their mothers (all samples collected at deli very). The data show that the variants detected between birth and the third month of life in samples from the four newborns were present in the HCV po pulations of their mothers at delivery. In the newborns, a unique viral var iant (or a small group of closely related variants) remained stable for wee ks despite active viral replication. Diversification of the intrahost HCV p opulation was observed 6 to 13 months after birth and was substantially hig her in two of the four subjects, as documented by the intersample genetic d istance (GD) (P = 0.007). Importantly, a significant correlation between in creasing GD and high values for the intersample K-a/K-s ratio (the ratio be tween antonymous and synonymous substitutions; an index of the action of se lective forces) was observed, as documented by the increase of both paramet ers over time (P = 0.01). These data argue for a dominant role of positive selection for amino acid changes in driving the pattern of genetic diversif ication of HCV populations, indicate that the intrahost evolution of HCV po pulations is compatible with a Darwinian model system, and may have implica tions in the designing of future antiviral strategies.