The Potential for Respiratory Droplet-Transmissible A/H5N1 Influenza Virus to Evolve in a Mammalian Host

Department of Zoology, University of Cambridge, Cambridge, UK.
Science (Impact Factor: 33.61). 06/2012; 336(6088):1541-7. DOI: 10.1126/science.1222526
Source: PubMed


Avian A/H5N1 influenza viruses pose a pandemic threat. As few as five amino acid substitutions, or four with reassortment, might be sufficient for mammal-to-mammal transmission through respiratory droplets. From surveillance data, we found that two of these substitutions are common in A/H5N1 viruses, and thus, some viruses might require only three additional substitutions to become transmissible via respiratory droplets between mammals. We used a mathematical model of within-host virus evolution to study factors that could increase and decrease the probability of the remaining substitutions evolving after the virus has infected a mammalian host. These factors, combined with the presence of some of these substitutions in circulating strains, make a virus evolving in nature a potentially serious threat. These results highlight critical areas in which more data are needed for assessing, and potentially averting, this threat.

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    • "). Based on current scientific knowledge, risk screening might also incorporate high-throughput virologic and genetic screens used to identify isolates of concern by looking for genetic changes associated with altered binding affinities and other markers of transmission in mammals (Russell et al., 2012 "
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    ABSTRACT: The controversy surrounding 'gain-of-function' experiments on high-consequence avian influenza viruses has highlighted the role of ferret transmission experiments in studying the transmission potential of novel influenza strains. However, the mapping between influenza transmission in ferrets and in humans is unsubstantiated. We address this gap by compiling and analyzing 240 estimates of influenza transmission in ferrets and humans. We demonstrate that estimates of ferret secondary attack rate (SAR) explain 66% of the variation in human SAR estimates at the subtype level. Further analysis shows that ferret transmission experiments have potential to identify influenza viruses of concern for epidemic spread in humans, though small sample sizes and biological uncertainties prevent definitive classification of human transmissibility. Thus, ferret transmission experiments provide valid predictions of pandemic potential of novel influenza strains, though results should continue to be corroborated by targeted virological and epidemiological research.
    eLife Sciences 09/2015; 4. DOI:10.7554/eLife.07969 · 9.32 Impact Factor
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    • "Public health concerns have mostly centered on the potential of contemporary avian influenza subtype viruses to mutate or reassort with other influenza subtypes to a form that could become transmissible among humans. As a result, multiple studies have been performed to assess the molecular determinants of avian H5, H7 and H9 virus adaptation, pathogenicity and transmissibility in mammalian hosts (Maines et al., 2006; Salomon et al., 2006; Chen et al., 2012; Russell et al., 2012; Herfst et al., 2012; Sorrell et al., 2009). However, relatively less attention has been given to H2 subtype viruses largely due to their sporadic isolation and low pathogenicity in both avian and mammalian species (Pappas et al., 2010; Jones et al., 2014). "
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    ABSTRACT: After their disappearance from the human population in 1968, influenza H2 viruses have continued to circulate in the natural avian reservoir. The isolation of this virus subtype from multiple bird species as well as swine highlights the need to better understand the potential of these viruses to spread and cause disease in humans. Here we analyzed the virulence, transmissibility and receptor-binding preference of two avian influenza H2 viruses (H2N2 and H2N3) and compared them to a swine H2N3 (A/swine/Missouri/2124514/2006 [swMO]), and a human H2N2 (A/England/10/1967 [Eng/67]) virus using the ferret model as a mammalian host. Both avian H2 viruses possessed the capacity to spread efficiently between cohoused ferrets, and the swine (swMO) and human (Eng/67) viruses transmitted to naïve ferrets by respiratory droplets. Further characterization of the swMO hemagglutinin (HA) by x-ray crystallography and glycan microarray array identified receptor-specific adaptive mutations. As influenza virus quasispecies dynamics during transmission have not been well characterized, we sequenced nasal washes collected during transmission studies to better understand experimental adaptation of H2 HA. The avian H2 viruses isolated from ferret nasal washes contained mutations in the HA1, including a Gln226Leu substitution, which is a mutation associated with α2,6 sialic acid (human-like) binding preference. These results suggest that the molecular structure of HA in viruses of the H2 subtype continue to have the potential to adapt to a mammalian host and become transmissible, after acquiring additional genetic markers.
    Virology 03/2015; 477. DOI:10.1016/j.virol.2015.01.002 · 3.32 Impact Factor
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    • "Two of these 4 mutations (N158D and N224K) have lost their glycosylation sequons (Imai et al., 2012). Furthermore, the substitutions of the glycosylation sequon on HA have drifted in and out of the avian virus population over time, which might have been caused by little selective pressure (Russell et al., 2012). In addition, additional glycans in the globular head of HA resulted in substantially attenuated infection in H1N1 virus (Kim et al., 2013; Medina et al., 2013). "
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    ABSTRACT: Cleavage of the hemagglutinin (HA) precursor (HA0) by trypsin, which produces the active HA1 and HA2 complex, is a critical step for activating the avian influenza virus (AIV). However, other tryptic cleavage sites on HA might also cause HA degradation and affect the virulence. Otherwise, HA is modified by glycosylation in the host cell. The conjugated glycans on HA may hinder the antigenic epitopes, and thus prevent the virus from being recognized and attacked by the antibodies. In this study, we observed that glycosylation at the Asn-167 (N167) site on the HA1 of the H6N1 AIV strain A/chicken/Taiwan/2838V/00 (2838V) protected Arg-201 (R201) from tryptic cleavage. The 2838V HA protein became sensitive to tryptic cleavage, whereas the glycans at N167 were removed by N-glycosidase F (PNGase-F). Furthermore, the infectivity of 2838V decreased when pretreated with PNGase-F and trypsin. Our observations suggest that the inaccessibility of the R201 residue of HA1 for tryptic cleavage, which is sterically hindered by glycosylation at N167, is a crucial factor for determining the infectivity of the AIV. Copyright © 2014. Published by Elsevier B.V.
    Virus Research 02/2015; 197:101-107. DOI:10.1016/j.virusres.2014.12.010 · 2.32 Impact Factor
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