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Deep sequencing reveals mixed infection with 2009 pandemic influenza A (H1N1) virus strains and the emergence of oseltamivir resistance.

ABSTRACT: Mixed infections with seasonal influenza A virus strains are a common occurrence and an important source of genetic diversity. Prolonged viral shedding, as observed in immunocompromised individuals, can lead to mutational accumulation over extended periods. Recently, drug resistance was reported in immunosuppressed patients infected with the 2009 pandemic influenza A (H1N1) virus within a few days after oseltamivir treatment was initiated. To better understand the evolution and emergence of drug resistance in these circumstances, we used a deep sequencing approach to survey the viral population from an immunosuppressed patient infected with H1N1/2009 influenza and treated with neuraminidase inhibitors. This patient harbored 3 genetic variants from 2 phylogenetically distinct viral clades of pandemic H1N1/2009, strongly suggestive of mixed infection. Strikingly, one of these variants also developed drug resistance de novo in response to oseltamivir treatment. Immunocompromised individuals may, therefore, constitute an important source of genetic and phenotypic diversity, both through mixed infection and de novo mutation.

SUBMITTER: Ghedin E

PROVIDER: S-EPMC3071067 | biostudies-literature | 2011 Jan

REPOSITORIES: biostudies-literature

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Deep sequencing reveals mixed infection with 2009 pandemic influenza A (H1N1) virus strains and the emergence of oseltamivir resistance.

Ghedin Elodie E Laplante Jennifer J DePasse Jay J Wentworth David E DE Santos Roberto P RP Lepow Martha L ML Porter Joanne J Stellrecht Kathleen K Lin Xudong X Operario Darwin D Griesemer Sara S Fitch Adam A Halpin Rebecca A RA Stockwell Timothy B TB Spiro David J DJ Holmes Edward C EC St George Kirsten K

The Journal of infectious diseases 20110101 2

Mixed infections with seasonal influenza A virus strains are a common occurrence and an important source of genetic diversity. Prolonged viral shedding, as observed in immunocompromised individuals, can lead to mutational accumulation over extended periods. Recently, drug resistance was reported in immunosuppressed patients infected with the 2009 pandemic influenza A (H1N1) virus within a few days after oseltamivir treatment was initiated. To better understand the evolution and emergence of drug ...[more]

PMID: 21288815

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Project description:Pandemic (H1N1) 2009 influenza is affecting countries in all five continents, with most cases so far having been reported in North and South America and Europe, and children and young adults being the most susceptible age groups. To date, the clinical course of disease is typically mild, with low hospitalization and mortality rates. Pandemic (H1N1) 2009 is susceptible to oseltamivir and, although few clinical data are yet available, current information suggests that treatment with oseltamivir appears to be beneficial. Only isolated cases of resistance to the drug have been reported to date, in keeping with the low frequency observed in clinical studies involving patients infected with seasonal influenza viruses. Current health authority guidelines recommend the use of oseltamivir in infected adults and children who have or are at elevated risk for severe disease, including pregnant women; use during the pandemic in infants < 1 year has also been authorized in Europe and a number of other countries, including the USA and Canada. Before the onset of the current pandemic, F. Hoffmann-La Roche Ltd expanded annual production capacity for oseltamivir to 400 million treatment courses per year to meet anticipated demand. However, during an influenza pandemic, and despite increased production capabilities, resources are nonetheless likely to be initially in short supply. For this reason, Roche, in line with WHO recommendations, has advocated advance stockpiling of antivirals by governments as a pandemic preparedness measure. Between 2004 and December 2009, 350 million treatment courses were supplied to governments worldwide. Support for developing countries has been a priority. Roche has established a cluster of initiatives aimed at increasing access to Tamiflu for the world's developing economies, including, making donations to the WHO, establishing the Tamiflu Reserves Program (TRP) and sub-licensing and manufacturing contracts with local companies in Asia and Africa. Furthermore, Roche has published a document outlining how it would allocate limited supplies of Tamiflu during a pandemic, which are in line with WHO recommendations stating that 'resources should be used to provide the maximum possible health benefit'. Roche is also offering support such as reprocessing of expiring capsule stocks (in development) and shelf-life extension to support governments in the management of their stockpiles. Clinical studies, either sponsored by or supported by Roche, are in progress. These trials are designed to investigate the effectiveness of oseltamivir in patients infected with the pandemic virus in greater depth, and include high-dose studies, assessment of natural and drug-induced resistance, and response to treatment in high-risk populations such as young infants, immunocompromised patients and the severely ill.

Project description:The neuraminidase (NA) inhibitor oseltamivir offers an important immediate option for the control of influenza, and its clinical use has increased substantially during the recent H1N1 pandemic. In view of the high prevalence of oseltamivir-resistant seasonal H1N1 influenza viruses in 2007-2008, there is an urgent need to characterize the transmissibility and fitness of oseltamivir-resistant H1N1/2009 viruses, although resistant variants have been isolated at a low rate. Here we studied the transmissibility of a closely matched pair of pandemic H1N1/2009 clinical isolates, one oseltamivir-sensitive and one resistant, in the ferret model. The resistant H275Y mutant was derived from a patient on oseltamivir prophylaxis and was the first oseltamivir-resistant isolate of the pandemic virus. Full genome sequencing revealed that the pair of viruses differed only at NA amino acid position 275. We found that the oseltamivir-resistant H1N1/2009 virus was not transmitted efficiently in ferrets via respiratory droplets (0/2), while it retained efficient transmission via direct contact (2/2). The sensitive H1N1/2009 virus was efficiently transmitted via both routes (2/2 and 1/2, respectively). The wild-type H1N1/2009 and the resistant mutant appeared to cause a similar disease course in ferrets without apparent attenuation of clinical signs. We compared viral fitness within the host by co-infecting a ferret with oseltamivir-sensitive and -resistant H1N1/2009 viruses and found that the resistant virus showed less growth capability (fitness). The NA of the resistant virus showed reduced substrate-binding affinity and catalytic activity in vitro and delayed initial growth in MDCK and MDCK-SIAT1 cells. These findings may in part explain its less efficient transmission. The fact that the oseltamivir-resistant H1N1/2009 virus retained efficient transmission through direct contact underlines the necessity of continuous monitoring of drug resistance and characterization of possible evolving viral proteins during the pandemic.

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Deep sequencing reveals mixed infection with 2009 pandemic influenza A (H1N1) virus strains and the emergence of oseltamivir resistance.

Publications

Deep sequencing reveals mixed infection with 2009 pandemic influenza A (H1N1) virus strains and the emergence of oseltamivir resistance.

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