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Dominant role of host selective pressure in driving hepatitis C virus evolution in perinatal infection
A Manzin1, L Solforosi, M Debiaggi
1Institute of Microbiology, University of Ancona, Ancona, Italy. manzin@popcsi.unian.it
Insights
Hepatitis C virus (HCV) genetic diversification in newborns shows early maternal transmission. Positive selection drives viral evolution, suggesting Darwinian principles and impacting antiviral strategies.
Area of Science:
- Virology
- Evolutionary Biology
- Genetics
Background:
- Hepatitis C virus (HCV) poses a significant global health challenge.
- Understanding HCV genetic diversification is crucial for effective treatment and prevention.
- Perinatal transmission represents a key route for HCV infection in newborns.
Purpose of the Study:
- To investigate the genetic diversification dynamics of Hepatitis C virus (HCV) populations during perinatal infection.
- To analyze the evolutionary patterns of HCV in newborns and their mothers.
- To determine the role of selection pressures in shaping intrahost HCV evolution.
Main Methods:
- Obtaining clonal sequences of the hypervariable region 1 (HVR1) of the E2 envelope protein of HCV.
- Analyzing sequential samples from four HCV-infected newborns and their mothers.
- Quantifying genetic diversification using intersample genetic distance (GD) and the K(a)/K(s) ratio.
Main Results:
- HCV variants in newborns at birth were present in maternal populations.
- A stable dominant viral variant was observed in newborns for weeks despite replication.
- Significant genetic diversification and positive selection were evident 6-13 months post-birth, particularly in two subjects.
- A correlation between increasing genetic distance and the K(a)/K(s) ratio indicated positive selection driving diversification.
Conclusions:
- HCV intrahost evolution follows Darwinian principles, driven by positive selection for amino acid changes.
- Early HCV variants in newborns originate from maternal viral populations.
- Findings have implications for developing novel antiviral strategies targeting HCV evolution.
Abstract:
The dynamics of the genetic diversification of hepatitis C virus (HCV) populations was addressed in perinatal infection. Clonal sequences of hypervariable 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 13 months after birth) and from their mothers (all samples collected at delivery). 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 populations of their mothers at delivery. In the newborns, a unique viral variant (or a small group of closely related variants) remained stable for weeks despite active viral replication. Diversification of the intrahost HCV population was observed 6 to 13 months after birth and was substantially higher in two of the four subjects, as documented by the intersample genetic distance (GD) (P = 0.007). Importantly, a significant correlation between increasing GD and high values for the intersample K(a)/K(s) ratio (the ratio between anoffymous and synonymous substitutions; an index of the action of selective forces) was observed, as documented by the increase of both parameters 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 diversification of HCV populations, indicate that the intrahost evolution of HCV populations is compatible with a Darwinian model system, and may have implications in the designing of future antiviral strategies.