Sun-Woo Yoon - Academia.edu (original) (raw)

Papers by Sun-Woo Yoon

The Journal of Infectious Diseases, 2017

Proceedings of the National Academy of Sciences of the United States of America, Jan 14, 2016

The influenza endonuclease is an essential subdomain of the viral RNA polymerase. It processes ho... more The influenza endonuclease is an essential subdomain of the viral RNA polymerase. It processes host pre-mRNAs to serve as primers for viral mRNA and is an attractive target for antiinfluenza drug discovery. Compound L-742,001 is a prototypical endonuclease inhibitor, and we found that repeated passaging of influenza virus in the presence of this drug did not lead to the development of resistant mutant strains. Reduced sensitivity to L-742,001 could only be induced by creating point mutations via a random mutagenesis strategy. These mutations mapped to the endonuclease active site where they can directly impact inhibitor binding. Engineered viruses containing the mutations showed resistance to L-742,001 both in vitro and in vivo, with only a modest reduction in fitness. Introduction of the mutations into a second virus also increased its resistance to the inhibitor. Using the isolated wild-type and mutant endonuclease domains, we used kinetics, inhibitor binding and crystallography t...

Vaccine, Jan 18, 2015

The recently detected zoonotic H3N2 variant influenza A (H3N2v) viruses have caused 343 documente... more The recently detected zoonotic H3N2 variant influenza A (H3N2v) viruses have caused 343 documented cases of human infection linked to contact with swine. An effective vaccine is needed for these viruses, which may acquire transmissibility among humans. However, viruses isolated from human cases do not replicate well in embryonated chicken eggs, posing an obstacle to egg-based vaccine production. To address this issue, we sought to identify egg-adaptive mutations in surface proteins that increase the yield of candidate vaccine viruses (CVVs) in eggs while preserving their immunizing effectiveness. After serial passage of a representative H3N2v isolate (A/Indiana/08/2011), we identified several egg-adaptive combinations of HA mutations and assessed the egg-based replication, antigenicity, and immunogenicity of A/Puerto Rico/8/34 (H1N1, PR8)-based 6+2 reverse genetics CVVs carrying these mutations. Here we demonstrate that the respective combined HA substitutions G1861V+N2461K, N1651K+...

Virology, 2014

The cleavage motif in the hemagglutinin (HA) protein of highly pathogenic H5 and H7 subtypes of a... more The cleavage motif in the hemagglutinin (HA) protein of highly pathogenic H5 and H7 subtypes of avian influenza viruses is characterized by a peptide insertion or a multibasic cleavage site (MBCS). Here, we isolated an H4N2 virus from quails (Quail/CA12) with two additional arginines in the HA cleavage site, PEKRRTR/G, forming an MBCS-like motif. Quail/CA12 is a reassortant virus with the HA and neuraminidase (NA) gene most similar to a duck-isolated H4N2 virus, PD/CA06 with a monobasic HA cleavage site. Quail/CA12 required exogenous trypsin for efficient growth in culture and caused no clinical illness in infected chickens. Quail/CA12 had high binding preference for α2,6-linked sialic acids and showed higher replication and transmission ability in chickens and quails than PD/CA06. Although the H4N2 virus remained low pathogenic, these data suggests that the acquisition of MBCS in the field is not restricted to H5 or H7 subtypes.

Vaccine, 2014

The H7N9 influenza virus caused significant mortality and morbidity in infected humans during an ... more The H7N9 influenza virus caused significant mortality and morbidity in infected humans during an outbreak in China in 2013 stimulating vaccine development efforts. As previous H7-based vaccines have been poorly immunogenic in humans we sought to determine the immunogenic and protective properties of an inactivated whole virus vaccine derived from a 2013 H7N9 virus in ferrets. As whole virus vaccine preparations have been shown to be more immunogenic in humans, but less likely to be used, than split or surface antigen formulations, we vaccinated ferrets with a single dose of 15, 30, or 50 μg of the vaccine and subsequently challenged with wild-type A/Anhui/1/2013 (H7N9) either by direct instillation or by contact with infected animals. Although ferrets vaccinated with higher doses of vaccine had higher serum hemagglutinin inhibition (HI) titers, the titers were still low. During subsequent instillation challenge, however, ferrets vaccinated with 50 μg of vaccine showed no illness and shed significantly less virus than mock vaccinated controls. All vaccinated ferrets had lower virus loads in their lungs as compared to controls. In a separate study where unvaccinated-infected ferrets were placed in the same cage with vaccinated-uninfected ferrets, vaccination did not prevent infection in the contact ferrets, although they showed a trend of lower viral load. Overall, we conclude that inactivated wholevirus H7N9 vaccine was able to reduce the severity of infection and viral load, despite the lack of hemagglutinin-inhibiting antibodies.

Nature Communications, 2014

The ongoing human H7N9 influenza infections highlight the threat of emerging avian influenza viru... more The ongoing human H7N9 influenza infections highlight the threat of emerging avian influenza viruses. In 2011, an avian H3N8 influenza virus isolated from moribund New England harbour seals was shown to have naturally acquired mutations known to increase the transmissibility of highly pathogenic H5N1 influenza viruses. To elucidate the potential human health threat, here we evaluate a panel of avian H3N8 viruses and find that the harbour seal virus displays increased affinity for mammalian receptors, transmits via respiratory droplets in ferrets and replicates in human lung cells. Analysis of a panel of human sera for H3N8 neutralizing antibodies suggests that there is no population-wide immunity to these viruses. The prevalence of H3N8 viruses in birds and multiple mammalian species including recent isolations from pigs and evidence that it was a past human pandemic virus make the need for surveillance and risk analysis of these viruses of public health importance.

Proceedings of the National Academy of Sciences, 2011

The emergence of the unique H1N1 influenza A virus in 2009 resulted in a pandemic that has spread... more The emergence of the unique H1N1 influenza A virus in 2009 resulted in a pandemic that has spread to over 200 countries. The constellation of molecular factors leading to the emergence of this strain is still unclear. Using a computational approach, we identified molecular determinants that may discriminate the hemagglutinin protein of the 2009 human pandemic H1N1 (pH1N1) strain from that of other H1N1 strains. As expected, positions discriminating the pH1N1 from seasonal human strains were located in or near known H1N1 antigenic sites, thus camouflaging the pH1N1 strain from immune recognition. For example, the alteration S145K (an antigenic position) was found as a characteristic of the pH1N1 strain. We also detected positions in the hemagglutinin protein differentiating classical swine viruses from pH1N1. These positions were mostly located in and around the receptor-binding pocket, possibly influencing binding affinity to the human cell. Such alterations may be liable in part fo...

Journal of Virology, 2013

Highly pathogenic avian influenza (HPAI) virus H5N1 has been enzootic in Egypt since 2008. Virus-... more Highly pathogenic avian influenza (HPAI) virus H5N1 has been enzootic in Egypt since 2008. Virus-associated mortality (but not the number of cases) in humans and poultry seems to have decreased over time, but the reason for this remains unknown. We investigated the role of a single amino acid substitution in the hemagglutinin cleavage site on virus pathogenicity and transmission in chickens. The R325G substitution significantly reduced pathogenicity without altering the transmission efficiency of HPAI H5N1 virus.