N-Linked Glycosylation Attenuates H3N2 Influenza Viruses

Vigerust, David J.; Ulett, Kimberly B.; Boyd, Kelli L.; Madsen, Jens; Hawgood, Samuel; McCullers, Jonathan A.

doi:10.1128/jvi.00769-07

Cited by 157 publications

(190 citation statements)

References 49 publications

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“…Interestingly, as the level of glycosylation on influenza H3N2 has increased since 1968, the morbidity, mortality, and viral lung titers have decreased (26). Our finding that HA with a single GlcNAc attached to the glycosylation sites showed relaxed specificity but enhanced affinity to ␣2,3 sialosides suggests that the N-glycans on HA may cause steric hindrance near the HA-receptor binding domain.…”

Section: Discussionmentioning

confidence: 65%

Glycans on influenza hemagglutinin affect receptor binding and immune response

Wang

Chen

Tseng

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

283

256

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Recent cases of avian influenza H5N1 and the swine-origin 2009 H1N1 have caused a great concern that a global disaster like the 1918 influenza pandemic may occur again. Viral transmission begins with a critical interaction between hemagglutinin (HA) glycoprotein, which is on the viral coat of influenza, and sialic acid (SA) containing glycans, which are on the host cell surface. To elucidate the role of HA glycosylation in this important interaction, various defined HA glycoforms were prepared, and their binding affinity and specificity were studied by using a synthetic SA microarray. Truncation of the N-glycan structures on HA increased SA binding affinities while decreasing specificity toward disparate SA ligands. The contribution of each monosaccharide and sulfate group within SA ligand structures to HA binding energy was quantitatively dissected. It was found that the sulfate group adds nearly 100-fold (2.04 kcal/mol) in binding energy to fully glycosylated HA, and so does the biantennary glycan to the monoglycosylated HA glycoform. Antibodies raised against HA protein bearing only a single N-linked GlcNAc at each glycosylation site showed better binding affinity and neutralization activity against influenza subtypes than the fully glycosylated HAs elicited. Thus, removal of structurally nonessential glycans on viral surface glycoproteins may be a very effective and general approach for vaccine design against influenza and other human viruses.flu vaccine ͉ glycan binding ͉ glycosylation T he highly pathogenic H5N1 and the 2009 swine-origin influenza A (H1N1) viruses have caused global outbreaks and raised a great concern that further changes in the viruses may occur to bring about a deadly pandemic (1, 2). Important contributions to our understanding of influenza infections have come from the studies on hemagglutinin (HA), a viral coat glycoprotein that binds to specific sialylated glycan receptors in the respiratory tract, allowing the virus to enter the cell (3-6). To cross the species barrier and infect the human population, avian HA must change its receptorbinding preference from a terminally sialylated glycan that contains ␣2,3 (avian)-linked to ␣2,6 (human)-linked sialic acid motifs (7), and this switch could occur through only two mutations, as in the 1918 pandemic (8). Understanding the factors that affect influenza binding to glycan receptors is thus critical for developing methods to control any future crossover influenza strains that have pandemic potential.HA is a homotrimeric transmembrane protein with an ectodomain composed of a globular head and a stem region (3). Both regions carry N-linked oligosaccharides (9), which affect the functional properties of HA (10, 11). Among different subtypes of influenza A viruses, there is extensive variation in the glycosylation sites of the head region, whereas the stem oligosaccharides are more conserved and required for fusion activity (11). Glycans near antigenic peptide epitopes interfere with antibody recognition (12), and glycans near the proteolytic ...

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Section: Discussionmentioning

confidence: 65%

Glycans on influenza hemagglutinin affect receptor binding and immune response

Wang

Chen

Tseng

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

283

256

View full text Add to dashboard Cite

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“…These sequons, located in the stalk region of HA1, have become conserved in preceeding strains. There has been an accumulation of sequons, mainly in the globular head of HA, in strains proceeding the first occurring pandemic viruses 22 , 23 , 24 …”

Section: Resultsmentioning

confidence: 99%

“…We have shown that the pandemic HA genes in our DNA vaccines possess the least amount of glycosylations. These sequons have become conserved since then, while preceeding strains have gained additional sequons, mainly in the globular head 22 , 23 , 24 . Therefore, the cross‐reactivity of the pandemic DNA vaccine genes with more recent strains could be related to the limited number of glycosylation sites.…”

Section: Discussionmentioning

confidence: 99%

Pandemic influenza 1918 H1N1 and 1968 H3N2 DNA vaccines induce cross-reactive immunity in ferrets against infection with viruses drifted for decades

Bragstad

Martel

Thomsen

et al. 2010

Influenza and Other Respiratory Viruses

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Please cite this paper as: Bragstad et al. (2010) Pandemic influenza 1918 H1N1 and 1968 H3N2 DNA vaccines induce cross‐reactive immunity in ferrets against infection with viruses drifted for decades. Influenza and Other Respiratory Viruses 5(1), 13–23. Background Alternative influenza vaccines and vaccine production forms are needed as the conventional protein vaccines do not induce broad cross‐reactivity against drifted strains. Furthermore, fast vaccine production is especially important in a pandemic situation, and broader vaccine reactivity would diminish the need for frequent change in the vaccine formulations. Objective In this study, we compared the ability of pandemic influenza DNA vaccines to induce immunity against distantly related strains within a subtype with the immunity induced by conventional trivalent protein vaccines against homologous virus challenge. Methods Ferrets were immunised by particle‐mediated epidermal delivery (gene gun) with DNA vaccines based on the haemagglutinin (HA) and neuraminidase (NA) and/or the matrix (M) and nucleoprotein genes of the 1918 H1N1 Spanish influenza pandemic virus or the 1968 H3N2 Hong Kong influenza pandemic virus. The animals were challenged with contemporary H1N1 or H3N2 viruses. Results We demonstrated that DNA vaccines encoding proteins of the original 1918 H1N1 pandemic virus induced protective cross‐reactive immune responses in ferrets against infection with a 1947 H1N1 virus and a recent 1999 H1N1 virus. Similarly, a DNA vaccine, based on the HA and NA of the 1968 H3N2 pandemic virus, induced cross‐reactive immune responses against a recent 2005 H3N2 virus challenge. Conclusions DNA vaccines based on pandemic or recent seasonal influenza genes induced cross‐reactive immunity against contemporary virus challenge as good as or superior to contemporary conventional trivalent protein vaccines. This suggests a unique ability of influenza DNA to induce cross‐protective immunity against both contemporary and long‐time drifted viruses.

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“…The mouse‐adapted Mount Sinai strain of A/Puerto Rico/8/34 (PR8) is an H1N1 subtype virus taken from the influenza virus repository at St. Jude Children’s Research Hospital. To determine whether findings were subtype specific, a second virus was generated using the eight plasmid reverse genetics system 13 which contains the H3 hemagglutinin (HA) and N2 neuraminidase (NA) from A/Hong/Kong/1/68 (HK68; H3N2) and the six internal genes of PR8 as described 14 . The PR8 backbone was utilized to enhance virulence in mice as the wild‐type parent HK68 causes only mild disease and is not lethal.…”

mentioning

confidence: 99%

Chloroquine is effective against influenza A virus in vitro but not in vivo

Vigerust

McCullers

2007

Influenza Resp Viruses

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Background Chloroquine is an inexpensive and widely available 9‐aminoquinolone used in the management of malaria. Recently, in vitro assays suggest that chloroquine may have utility in the treatment of several viral infections including influenza. Objectives We sought to test whether chloroquine is effective against influenza in vivo in relevant animal models. Methods The effectiveness of chloroquine at preventing or ameliorating influenza following viral challenge was assessed in established mouse and ferret disease models. Results Although active against influenza viruses in vitro, chloroquine did not prevent the weight loss associated with influenza virus infection in mice after challenge with viruses expressing an H1 or H3 hemagglutinin protein. Similarly, clinical signs and viral replication in the nose of ferrets were not altered by treatment. Conclusions Although in vitro results were promising, chloroquine was not effective as preventive therapy in vivo in standard mouse and ferret models of influenza virus infection. This dampens enthusiasm for the potential utility of the drug for humans with influenza.

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N-Linked Glycosylation Attenuates H3N2 Influenza Viruses

Cited by 157 publications

References 49 publications

Glycans on influenza hemagglutinin affect receptor binding and immune response

Glycans on influenza hemagglutinin affect receptor binding and immune response

Pandemic influenza 1918 H1N1 and 1968 H3N2 DNA vaccines induce cross-reactive immunity in ferrets against infection with viruses drifted for decades

Chloroquine is effective against influenza A virus in vitro but not in vivo

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