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

Abstract

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.

Oseltamivir‐resistant influenza A(H1N1)pdm09 virus associated with high case fatality, India 2015

“…From the study performed in US community cluster, Australia, Japan, Brazil the same observations found. However presence of N386K mutation was not found in Australia and Japan and its role in viral fitness is still controversial …”

Inhibitory effect of microalgae and cyanobacteria extracts on influenza virus replication and neuraminidase activity

“…The OST is the main antiviral used in clinics against Influenza A and B. The pressure imposed by this drug has led to the selection of resistant mutants ( Dixit et al, 2013 ; Lopes e Souza et al, 2015 ; Souza et al, 2011 ). Thus, the search for new anti-influenza compounds that inhibits both types of influenza and their resistant strains or lineages is extremely important.…”

“…Wild-type and resistant strains of influenza A and B were tested against different concentrations of extracts (400 − 12.5 or 200 − 6.25 µg/mL), OST-car (1,000 − 0.01 nM) was used as control. This assay was done using the NA-Star™ assay kit (Life Technologies, USA), according to the manufacturer’s instructions ( Lopes e Souza et al, 2015 ; Souza et al, 2011 ; Souza et al, 2013 ). The IC50 was calculated using a non-linear regression.…”

“…Thus, the emergence of NAIs resistance could be a major clinical concern. Although most currently circulating influenza A and B strains are susceptible to NAIs, the pressure imposed by OST has led to the selection of OST-resistant mutants, with a prevalence of 1–2% in different countries ( Dixit et al, 2013 ; Lopes e Souza et al, 2015 ; Souza et al, 2011 ). The OST-resistant strains with compensatory mutations may arise in an independent fashion, with samples being identified in different states of Brazil and in other countries ( Lopes e Souza et al, 2015 ).…”

“…Although most currently circulating influenza A and B strains are susceptible to NAIs, the pressure imposed by OST has led to the selection of OST-resistant mutants, with a prevalence of 1–2% in different countries ( Dixit et al, 2013 ; Lopes e Souza et al, 2015 ; Souza et al, 2011 ). The OST-resistant strains with compensatory mutations may arise in an independent fashion, with samples being identified in different states of Brazil and in other countries ( Lopes e Souza et al, 2015 ). Reports have shown single or multiple substitutions or deletions in the NA gene, which can promote a phenotype cross-resistance to the two main NAIs (oseltamivir and zanamivir) used in clinics, mostly in immunocompromised individuals ( Abed & Boivin, 2017 ).…”