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

Hebah A Al Khatib,I Richard Thompson,Asmaa A Al Thani,Peter V Coyle,Hadi M Yassine,Muna A Al Maslamani,Elmoubasher A Farag

doi:10.3390/microorganisms8010133

Hebah A Al Khatib, I Richard Thompson + Show 5 more

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https://doi.org/10.3390/microorganisms8010133

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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.

Highlights

In April 2009, an H1N1 triple-reassortant swine-origin influenza virus was isolated from humans suffering from severe respiratory symptoms in North America [1]
Evolution of low-frequency variants over time and their emergence at the consensus level triggered us to investigate the possibility of this happening at the level of haplotypes; we studied the phylogenetic relationship between haplotypes of different patients over years
It is of prime importance to study virus evolution at sub-consensus and consensus levels as that will broaden our current knowledge of virus evolutionary dynamics

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In April 2009, an H1N1 triple-reassortant swine-origin influenza virus was isolated from humans suffering from severe respiratory symptoms in North America [1]. The virus later spread to more than 209 countries, resulting in about 14,711 deaths between April 2009 and January 2010 [2]. In August 2010, the H1N1 influenza pandemic was declared finished; the virus continued to circulate seasonally, replacing the former seasonal H1N1 viruses [3]. Influenza A viruses belong to the Orthomyxoviridae family and have a genome of eight single-stranded negative-sense RNA segments that encode 11 known proteins [4]. Polymerase subunits PB2, PB1, and PA are critical for replication and transcription of viral RNAs [5,6]. Due to the low-fidelity of PB1, the replication process is associated with a relatively high mutation rate (2.3 × 10−5), resulting in the huge genetic diversity often referred to as quasispecies [5,7,8]

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