Browsing by Author "Gíria, M."
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- Genetic evolution of PB1 in the zoonotic transmission of influenza A(H1) virusPublication . Gíria, M.; Rebelo-de-Andrade, H.The epidemiology of human infection with swine-origin influenza A(H1) viruses suggests that the virus must adapt to replicate and transmit within the human host. PB1 is essential to the replication process. The objective of this study was to identify whether PB1 retains genetic traces of interspecies transmission and adaptation. We have found that the evolutionary history of PB1 is traceable. Lineage appears to be distinguished by amino acid changes between the conserved motifs of the viral polymerase, which can have major impact in PB1 protein folding, and by changes in the expression of the Mitochondrial Targeting Sequence and in the predicted helical region, that putatively affect induction of cellular apoptosis by PB1-F2. Furthermore, we found genomic markers that possibly relate to viral adaptation to new hosts and to new cellular environment and, additionally, to an enhanced compatibility with HA. We found no specific trend in the amino acid substitutions. Viral fitness appears to be favored by less reactive amino acids in some positions, while in others more reactive ones are fixed. Also, more flexible conformations appear associated with higher protein stability in general, although often more restrictive conformations appear to have favored protein folding and binding. Several aspects of PB1 mapping domains and the specific roles and interaction of PB1, PB1-F2 and N40 with each other and with other viral proteins and host cellular molecules remain unclear. Tracing the genetic evolution is critical to further understand the mechanisms by which PB1 affects vital fitness and adaptation. This analysis now permits putative adaptive related polymorphisms to be experimentally evaluated for phenotypic impact.
- Influenza A(H1N1)pdm09 resistance and cross-decreased susceptibility to oseltamivir and zanamivir antiviral drugsPublication . Correia, V.; Santos, L.; Gíria, M.; Almeida-Santos, M.; Rebelo-de-Andrade, H.Neuraminidase inhibitors (NAIs) oseltamivir and zanamivir are currently the only effective antiviral drugs available worldwide for the management of influenza. The potential development of resistance is continually threatening their use, rationalizing and highlighting the need for a close and sustained evaluation of virus susceptibility. This study aimed to analyze and characterize the phenotypic and genotypic NAIs susceptibility profiles of A(H1N1)pdm09 viruses circulating in Portugal from 2009 to 2010/2011. A total of 144 cases of A(H1N1)pdm09 virus infection from community and hospitalized patients were studied, including three suspected cases of clinical resistance to oseltamivir. Oseltamivir resistance was confirmed for two of the suspected cases. Neuraminidase (NA) H275Y resistant marker was found in viruses from both cases but for one it was only present in 26.2% of virus population, raising questions about the minimal percentage of resistant virus that should be considered relevant. Cross-decreased susceptibility to oseltamivir and zanamivir (2-4 IC50 fold-change) was detected on viruses from two potentially linked community patients from 2009. Both viruses harbored the NA I223V mutation. NA Y155H mutation was found in 18 statistical non-outlier viruses from 2009, having no impact on virus susceptibility. The mutations at NA N369K and V241I may have contributed to the significantly higher baseline IC50 value obtained to oseltamivir for 2010/2011 viruses, compared to viruses from the pandemic period. These results may contribute to a better understanding of the relationship between phenotype and genotype, which is currently challenging, and to the global assessment of A(H1N1)pdm09 virus susceptibility profile and baseline level to NAIs.