PLoS ONE. Genomic Polymorphism of the Pandemic A (H1N1) Influenza Viruses Correlates with Viral Replication, Virulence, and Pathogenicity In Vitro and

[Giuseppe]

[Source: PLoS ONE, full text: (LINK). Abstract, edited.]

Genomic Polymorphism of the Pandemic A (H1N1) Influenza Viruses Correlates with Viral Replication, Virulence, and Pathogenicity In Vitro and In Vivo



Lili Xu et al.
by Lili Xu, Linlin Bao, Jianfang Zhou, Dayan Wang, Wei Deng, Qi Lv, Yila Ma, Fengdi Li, Huihui Sun, Lingjun Zhan, Hua Zhu, Chunmei Ma, Yuelong Shu, Chuan Qin


The novel pandemic A (H1N1) virus was first identified in Mexico in April 2009 and quickly spread worldwide. Like all influenzas, the H1N1 strain-specific properties of replication, virulence, and pathogenicity are a result of the particular genomic sequence and concerted expression of multiple genes. Thus, specific mutations may support increased virulence and may be useful as biomarkers of potential threat to human health. We performed comparative genomic analysis of ten strains of the 2009 pandemic A (H1N1) influenza viruses to determine whether genotypes associated with clinical phenotypes, which ranged from mild to severe illness and up to lethal. Virus replication capacity was tested for each strain in vitro using cultured epithelial cells, while virulence and pathogenicity were investigated in vivo using the BALB/c mouse model. The results indicated that A/Sichuan/1/2009 strain had significantly higher replication ability and virulence than the other strains, and five unique non-synonymous mutations were identified in important gene-encoding sequences. These mutations led to amino acid substitutions in HA (L32I), PA (A343T), PB1 (K353R and T566A), and PB2 (T471M), and may be critical molecular determinants for replication, virulence, and pathogenicity. Our results suggested that the replication capacity in vitro and virulence in vivo of the 2009 pandemic A (H1N1) viruses were not associated with the clinical phenotypes. This study offers new insights into the transmission and evolution of the 2009 pandemic A (H1N1) virus.
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[mixin]

Re: PLoS ONE. Genomic Polymorphism of the Pandemic A (H1N1) Influenza Viruses Correlates with Viral Replication, Virulence, and Pathogenicity In Vitro and In Vivo

This study has some rather interesting comments for those who only looked at the abstract.

Here are their unique amino acid mutations and the codon positions:
T471M (PB2)= C1412T
K353R, T566A (PB1)= A1058G, A1696G
A343T (PA)= G1027A
L32I (HA)= C145A

Of the 30-35 2011 GISAID PA, PB2 and PB1 segments; only Delaware/08 and Maryland/06 have the PA mutation. None of the 286 HA segments have L32I. They were a little more prevalent in 2010 and I didn't check 2009 yet. I looked at the HAs for those 3 from this year and 4 from last year; they all are in the clade with C144T, G640A,T658A,T1056C, G1403A, C1408T and a few others.

[snips from the study]
Survival rates for lab mice:
20% A/Sichuan/1/2009
60% A/California/04/2009
70% A/California/07/2009
50-70% A/Fujian/1/2009, A/Shanghai/1/2009, and A/Guangdong/SWL28/2009
100% A/Shandong/1/2009, A/Beijing/3/2009, A/Jiangsu/1/2009, A/Sichuan-Wenjiang/SWL456/2009

While previous studies have associated another mutation in the HA receptor binding domain, Asp222Gly, with enhanced virulence, it remains to be confirmed whether HA affinity for sialyl receptors is directly responsible for the enhanced virulence of the 2009 pandemic A (H1N1) influenza viruses.

PB1-F2, a short viral protein of approximately 90 amino acids expressed from a +1 reading frame in the PB1 gene segment, was also reported as another virulence determinant; the serine at position 66 in PB1-F2 was associated with increased disease pathology in a mouse model.

Interestingly, the 2009 pandemic A (H1N1) influenza viruses do not encode a PB1-F2 protein, due to the presence of three stop codons in the gene sequence. However, Wanitchang et al. and Hai et al. reported that reinstatement of PB1-F2 elicited a minimal effect on virulence of the pandemic A (H1N1) virus in various mammalian models.