Oseltamivir-resistant influenza A(H1N1)pdm2009 strains found in Brazil are endowed with permissive mutations, which compensate the loss of fitness imposed by antiviral resistance.
The 2009 pandemic influenza A virus outbreak led to the systematic use of the neuraminidase (NA) inhibitor oseltamivir (OST). Consequently, OST-resistant strains, carrying the mutation H275Y, emerged in the years after the pandemics, with a prevalence of 1-2%. Currently, OST-resistant strains have been found in community settings, in untreated individuals. To spread in community settings, H275Y mutants must contain additional mutations, collectively called permissive mutations. We display the permissive mutations in NA of OST-resistant A(H1N1)pdm09 virus found in Brazilian community settings. The NAs from 2013 are phylogenetically distinct from those of 2012, indicating a tendency of positive selection of NAs with better fitness. Some previously predicted permissive mutations, such as V241I and N369K, found in different countries, were also detected in Brazil. Importantly, the change D344N, also predicted to compensate loss of fitness imposed by H275Y mutation, was found in Brazil, but not in other countries in 2013. Our results reinforce the notion that OST-resistant A(H1N1)pdm09 strains with compensatory mutations may arise in an independent fashion, with samples being identified in different states of Brazil and in different countries. Systematic circulation of these viral strains may jeopardise the use of the first line of anti-influenza drugs in the future.
Laboratório de Vírus Respiratórios e do Sarampo.
Thiago Moreno
TM
Lopes e Souza
Laboratório de Vírus Respiratórios e do Sarampo.
Natalia
N
Fintelman-Rodrigues
Laboratório de Vírus Respiratórios e do Sarampo.
Paola Cristina
PC
Resende
Laboratório de Vírus Respiratórios e do Sarampo.
Milene
M
Mesquita
Fundação Estadual de Produção e Pesquisa em Saúde, Porto Alegre, RS, Brasil.
Tatiana Schaffer
TS
Gregianini
Instituto de Pesquisas Clínicas Evandro Chagas.
Fernando A
FA
Bozza
Instituto de Pesquisas Clínicas Evandro Chagas.
Ana Carla
AC
Pecego
Estado de Santa Catarina, Florianópolis, SC, Brasil.
Sandra Bianchini
SB
Fernandes
Instituto Octávio Magalhães, Fundação Ezequiel Dias, Belo Horizonte, MG, Brasil.
Ana Luisa Furtado
AL
Cury
Estado do Paraná, PR, Brasil.
Irina Nastassja
IN
Riediger
Laboratório de Vírus Respiratórios e do Sarampo.
Marilda M
MM
Siqueira
D000328:Adult; D000998:Antiviral Agents / Q000627:therapeutic use*; D001938:Brazil; D024882:Drug Resistance, Viral / Q000235:genetics*; D005260:Female; D006801:Humans; D053118:Influenza A Virus, H1N1 Subtype / Q000145:classification / Q000187:drug effects* / Q000235:genetics*; D007251:Influenza, Human / Q000188:drug therapy / Q000821:virology*; D009154:Mutation; D059645:Mutation Rate; D017817:Nasal Lavage Fluid / Q000821:virology; D009439:Neuraminidase / Q000235:genetics; D053139:Oseltamivir / Q000627:therapeutic use*; D010802:Phylogeny; D058974:Phylogeography; D012367:RNA, Viral / Q000302:isolation & purification
D000998:Antiviral Agents; D012367:RNA, Viral; D053139:Oseltamivir; D009439:Neuraminidase