Intra-host viral population dynamics during acute hepatitis E virus infection

Area of Science:

• Virology
• Evolutionary Biology
• Genomics

Background:

• Hepatitis E virus (HEV) is a leading cause of acute viral hepatitis globally.
• RNA viruses exhibit high intra-host variability, facilitating adaptation to immune responses, particularly in chronic infections.
• Limited knowledge exists on HEV intra-host evolution during the acute phase of infection.

Purpose of the Study:

• To investigate the intra-host evolution of HEV populations during acute, asymptomatic infection.
• To characterize viral diversity and mutational signatures in acute HEV-3 infections.
• To understand the dynamics of early viral evolution and variant selection.

Main Methods:

• Highly sensitive HEV amplicon sequencing of serum samples from asymptomatic blood donors.
• Characterization of intra-host viral diversity and mutational signatures.
• Longitudinal sampling to track temporal shifts in variant frequencies.

Main Results:

• Constrained overall intra-host diversity with recurrent substitutions identified.
• Four polymerase region mutations enriched among donors, with rescued replication defects in trans-complementation assays.
• Acute-phase populations showed lower single-nucleotide variants (SNVs) and absence of high-frequency variants compared to chronic infections.
• Premature stop codons and defective genomes were primarily detected during the acute phase.

Conclusions:

• HEV intra-host evolution is dynamic yet constrained during acute infection.
• Selective forces act early, driving the emergence of variants, including those with impaired replication.
• Findings provide mechanistic insights into early viral evolution and transient persistence of defective variants, laying groundwork for future clinical outcome studies.