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The K m values for the MUNANA substrate of most viruses from the 2007–2008 season sensitive to oseltamivir (9.0☑.2 μM) were significantly reduced as compared to those measured for the A/New Caledonia/20/99(H1N1) (NC99) and A/Solomon Islands/3/2006(H1N1) (SI06) vaccine strains and for sensitive H1N1 isolates from previous seasons (28.0☒.7 μM). The Michaelis-Menten constant (K m), which reflects the affinity for the substrate, and the V m, which reflects the activity of the enzyme, were determined ( Table 1). Kinetic analyses of sialidase activities of the neuraminidase were performed using the MUNANA fluorogenic substrate in the absence or presence of neuraminidase inhibitors on whole virus suspensions as described. Properties of the Neuraminidase of H1N1 Viruses from the 2007–2008 Season All resistant viruses harbored the H275Y substitution in their N1. All viruses were sensitive to zanamivir (IC50, 1.2 to 3.0 nM).
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Using a standard neuraminidase inhibition assay, the IC50 values for oseltamivir ranged from 1.3 to 5.9 nM for sensitive viruses and were much higher (IC50, 624 to 942 nM) for resistant viruses ( Table 1), as previously published,.
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To understand the molecular basis of the apparent fitness of the resistant H1N1 viruses that emerged during the 2007–2008, season we determined the enzymatic characteristics of their neuraminidase.Ī selection of H1N1 viruses isolated by the National Influenza Center (Northern-France) from specimens received in the frame of routine surveillance through the GROG sentinel network between weeks 35/2007 and 03/2008 ( Table 1) were studied. Clinical H1N1 isolates with the H275Y mutation were previously found to be generally less fit in terms of replication, infectivity for mice or ferrets, or transmission potential, , although the mutation had a less pronounced and variable effect on virus fitness for laboratory strains such as WSN or PR8 viruses or for H5N1 viruses, –. The current frequencies of resistant H1N1 viruses are not correlated with oseltamivir usage, which suggests that selective drug pressure has not been associated with continued transmission, although it may have been involved in their initial emergence. Resistant H1N1 viruses with the H275Y change have been isolated from patients treated with oseltamivir and more frequently in children, especially in Japan, the country with the highest per capita usage of oseltamivir. Resistance was linked to the H275Y mutation (H274Y in N2 numbering) of the N1 known to confer high level resistance to oseltamivir but not to the other anti-neuraminidase inhibitor, zanamivir (Relenza) –. These frequencies are in sharp contrast with those observed for H1N1 viruses during previous seasons (0 to <1%) –. In Europe, the prevalence varies between countries, with highest levels in Norway (66.5%) and France (46.6%).
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Currently, resistant viruses are most prevalent in Europe (25%) but less prevalent in the Americas (16%) or the Western Pacific region (4%). Surveillance of the antiviral susceptibility of influenza viruses in Europe revealed the emergence of influenza A(H1N1) viruses naturally resistant to the anti-neuraminidase inhibitor oseltamivir (Tamiflu).