Inter-Versus Intra-Host Sequence Diversity of pH1N1 and Associated Clinical Outcomes

Abstract

The diversity of RNA viruses dictates their evolution in a particular host, community or environment. Here, we reported within- and between-host pH1N1virus diversity at consensus and sub-consensus levels over a three-year period (2015–2017) and its implications on disease severity. A total of 90 nasal samples positive for the pH1N1 virus were deep-sequenced and analyzed to detect low-frequency variants (LFVs) and haplotypes. Parallel evolution of LFVs was seen in the hemagglutinin (HA) gene across three scales: among patients (33%), across years (22%), and at global scale. Remarkably, investigating the emergence of LFVs at the consensus level demonstrated that within-host virus evolution recapitulates evolutionary dynamics seen at the global scale. Analysis of virus diversity at the HA haplotype level revealed the clustering of low-frequency haplotypes from early 2015 with dominant strains of 2016, indicating rapid haplotype evolution. Haplotype sharing was also noticed in all years, strongly suggesting haplotype transmission among patients infected during a specific influenza season. Finally, more than half of patients with severe symptoms harbored a larger number of haplotypes, mostly in patients under the age of five. Therefore, patient age, haplotype diversity, and the presence of certain LFVs should be considered when interpreting illness severity. In addition to its importance in understanding virus evolution, sub-consensus virus diversity together with whole genome sequencing is essential to explain variabilities in clinical outcomes that cannot be explained by either analysis alone.

Genome characterization and mutation analysis of human influenza A virus in Thailand

“…The amino acid substitutions (N44S, V241I, and N369K) in the NA have been reported to facilitate the stability of the virus [ 54 ]. The I188T and N449D mutations in the NA found in this study are similar to those reported in the previous study [ 55 ]; however, the function of the mutations has not been well characterized ( Fig. 5F ).…”

Analysis of influenza a genomes and bacterial microbiota in upper respiratory tracts of influenza patients

“…The amino acid substitutions (N44S, V241I, and N369K) in the NA have been reported to facilitate the stability of the virus (135). The I188T and N449D mutations in the NA found in this study are similar to those reported in the previous study (136); however, the function of the mutations has not been well characterized. Additionally, the nonsynonymous mutation at E55K, L90I, I123V, E125D, K131E, and N205S in the NS1 involve the inhibition of host gene expressions related to the interferon response (137,138).…”

Genetic diversity through social heterosis can increase virulence in RNA viral infections and cancer progression

“…(I7) RNA: Orthomyxoviridae influenza Patients with severe symptoms had a higher number of different viral haplotypes. [ 27 ] Diverse groups have higher productivity. (I2) RNA: Orthomyxoviridae influenza Intrahost diversity as a whole and on a specific set of gene segments increased with severity of outcome.…”

“…Synergistic interactions at the population level can also influence burst size, viral load and chronicity of infection [ 24 ]. The presence of certain variants in a population, even low-frequency ones, can play a large role in infection severity [ 27 ].…”