Quantifying relative within-host replication fitness in influenza virus competition experiments

Area of Science:

• Virology
• Evolutionary Biology
• Epidemiology

Background:

• Influenza virus resistance to antiviral drugs like oseltamivir arises from mutations in the neuraminidase gene.
• Assessing the fitness of drug-resistant strains relative to susceptible strains is crucial for surveillance and understanding viral evolution.
• Previous methods quantified relative in vivo fitness using co-infection models, assuming strain-dependent viral production rates.

Purpose of the Study:

• To extend a co-infection dynamics model for a more comprehensive analysis of fitness differences between competing virus strains.
• To re-analyze data on oseltamivir-resistant (OR) H1N1 pandemic 2009 (H1N1pdm09) viruses using the enhanced model.
• To investigate the impact of specific neuraminidase gene mutations on viral fitness.

Main Methods:

• Utilized a previously developed co-infection based method to assess relative in vivo fitness.
• Employed an extended within-host co-infection dynamics model to quantify fitness differences.
• Re-analyzed experimental data from competitive-mixtures of oseltamivir-resistant and oseltamivir-susceptible H1N1pdm09 viruses.

Main Results:

• The within-host replication fitness of oseltamivir-resistant H1N1pdm09 viruses was not compromised compared to oseltamivir-susceptible strains.
• Specific mutations (V241I and N369K) in the neuraminidase gene were found to significantly enhance the fitness of H1N1pdm09 OR viruses.
• The findings remained consistent irrespective of the hypothesized biological basis for the fitness differences.

Conclusions:

• Emergent oseltamivir-resistant H1N1pdm09 viruses exhibit robust fitness, challenging antiviral efficacy.
• Mutations V241I and N369K are key drivers of enhanced fitness in resistant strains, aiding their propagation.
• The refined modeling approach provides a more complete understanding of viral fitness and drug resistance dynamics.