Influenza HA Subtypes Demonstrate Divergent Phenotypes for Cleavage Activation and pH of Fusion: Implications for Host Range and Adaptation

Galloway, Summer E.; Reed, Mark L.; Russell, Charles J.; Steinhauer, David A.

doi:10.1371/journal.ppat.1003151

Cited by 186 publications

(261 citation statements)

References 79 publications

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“…Human pH1N1 viruses A/CA/04/2009 and A/TN/1-560/2009, which were isolated at the start of the pandemic, had mean an HA activation pH of 5.6 and 5.5, respectively (Fig. 1), which is moderately higher than the activation values (pH 5.0-5.3) of early pandemic viruses from the three 20th-century pandemics (10). Later pH1N1 viruses isolated from 2010 to 2012 were lower (pH 5.2-5.4), which is more in line with the 20th-century pandemic viruses.…”

Section: Resultsmentioning

confidence: 95%

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Molecular requirements for a pandemic influenza virus: An acid-stable hemagglutinin protein

Russier

Yang

Rehg

et al. 2016

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

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106

208

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Influenza pandemics require that a virus containing a hemagglutinin (HA) surface antigen previously unseen by a majority of the population becomes airborne-transmissible between humans. Although the HA protein is central to the emergence of a pandemic influenza virus, its required molecular properties for sustained transmission between humans are poorly defined. During virus entry, the HA protein binds receptors and is triggered by low pH in the endosome to cause membrane fusion; during egress, HA contributes to virus assembly and morphology. In 2009, a swine influenza virus (pH1N1) jumped to humans and spread globally. Here we link the pandemic potential of pH1N1 to its HA acid stability, or the pH at which this one-time-use nanomachine is either triggered to cause fusion or becomes inactivated in the absence of a target membrane. In surveillance isolates, our data show HA activation pH values decreased during the evolution of H1N1 from precursors in swine (pH 5.5–6.0), to early 2009 human cases (pH 5.5), and then to later human isolates (pH 5.2–5.4). A loss-of-function pH1N1 virus with a destabilizing HA1-Y17H mutation (pH 6.0) was less pathogenic in mice and ferrets, less transmissible by contact, and no longer airborne-transmissible. A ferret-adapted revertant (HA1-H17Y/HA2-R106K) regained airborne transmissibility by stabilizing HA to an activation pH of 5.3, similar to that of human-adapted isolates from late 2009–2014. Overall, these studies reveal that a stable HA (activation pH ≤ 5.5) is necessary for pH1N1 influenza virus pathogenicity and airborne transmissibility in ferrets and is associated with pandemic potential in humans.

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Section: Resultsmentioning

confidence: 95%

“…Measured HA activation pH values across all subtypes and species range from ∼5.0 to 6.0, trending higher in avian viruses (pH 5.6-6.0) and lower in human viruses (pH 5.0-5.5) (10).…”

mentioning

confidence: 97%

Molecular requirements for a pandemic influenza virus: An acid-stable hemagglutinin protein

Russier

Yang

Rehg

et al. 2016

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

Self Cite

106

208

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“…The HA from the pandemic 2009 H1N1 influenza A virus [A(H1N1)pdm09] has been reported to be less stable than the HAs of other seasonal influenza A virus strains (28)(29)(30)(31), a feature that likely contributes to challenges in the production of A(H1N1)pdm09 vaccines (28,29). Moreover, it was recently reported that the currently circulating A(H1N1)pdm09 virus is acquiring mutations that improve HA stability (31,32) and may therefore improve viral fitness.…”

Section: Influenza Virus Hemagglutinin (Ha) Is the Principal Antigenmentioning

confidence: 99%

Intermonomer Interactions in Hemagglutinin Subunits HA1 and HA2 Affecting Hemagglutinin Stability and Influenza Virus Infectivity

Wang

DeFeo

Alvarado-Facundo

et al. 2015

J Virol

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Influenza virus hemagglutinin (HA) mediates virus entry by binding to cell surface receptors and fusing the viral and endosomal membranes following uptake by endocytosis. The acidic environment of endosomes triggers a large-scale conformational change in the transmembrane subunit of HA (HA2) involving a loop (B loop)-to-helix transition, which releases the fusion peptide at the HA2 N terminus from an interior pocket within the HA trimer. Subsequent insertion of the fusion peptide into the endosomal membrane initiates fusion. The acid stability of HA is influenced by residues in the fusion peptide, fusion peptide pocket, coiled-coil regions of HA2, and interactions between the surface (HA1) and HA2 subunits, but details are not fully understood and vary among strains. Current evidence suggests that the HA from the circulating pandemic 2009 H1N1 influenza A virus [A(H1N1)pdm09] is less stable than the HAs from other seasonal influenza virus strains. Here we show that residue 205 in HA1 and residue 399 in the B loop of HA2 (residue 72, HA2 numbering) in different monomers of the trimeric A(H1N1)pdm09 HA are involved in functionally important intermolecular interactions and that a conserved histidine in this pair helps regulate HA stability. An arginine-lysine pair at this location destabilizes HA at acidic pH and mediates fusion at a higher pH, while a glutamate-lysine pair enhances HA stability and requires a lower pH to induce fusion. Our findings identify key residues in HA1 and HA2 that interact to help regulate H1N1 HA stability and virus infectivity. IMPORTANCE Influenza virus hemagglutinin (HA) is the principal antigen in inactivated influenza vaccines and the target of protective antibodies. However, the influenza A virus HA is highly variable, necessitating frequent vaccine changes to match circulating strains.Sequence changes in HA affect not only antigenicity but also HA stability, which has important implications for vaccine production, as well as viral adaptation to hosts. HA from the pandemic 2009 H1N1 influenza A virus is less stable than other recent seasonal influenza virus HAs, but the molecular interactions that contribute to HA stability are not fully understood. Here we identify molecular interactions between specific residues in the surface and transmembrane subunits of HA that help regulate the HA conformational changes needed for HA stability and virus entry. These findings contribute to our understanding of the molecular mechanisms controlling HA function and antigen stability. T he influenza virus envelope protein, hemagglutinin (HA), is organized as a noncovalently associated homotrimer on the viral surface. Each monomer of HA is posttranslationally cleaved into HA1 and HA2 subunits that are disulfide linked. The HA trimer consists of a large membrane-distal, globular domain formed only by HA1 and an elongated membrane-proximal stem domain comprised of HA2 and the N-and C-terminal segments of HA1. HA1 mediates virus binding to cell surface sialic acid receptors to initiate viral e...

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“…Avian and pandemic IAVs isolated in the years 1918, 1957 and 1968 have preserved its NA activity at low pH, while the epidemic viruses are not so stable at low pH (Takashi et al, 2012). Moreover, it was shown that the enzymatic activity of NA infl uences the in vitro fusion activity of HA, as the HA expressed from plasmid DNA mediates membrane fusion more eff ectively in the presence of NA and that the cleavage of sialic acid residues increases the HA-mediated membrane fusion (Su et al, 2009;Galloway et al, 2013). …”

Section: Other Iav Proteins Infl Uencing the Virulencementioning

confidence: 99%

The role of fusion activity of influenza A viruses in their biological properties

Jakubcová¹,

Hollý²,

Varečková³

2016

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Summary. -Infl uenza A viruses (IAVs) cause acute respiratory infections of humans, which are repeated yearly. Human IAV infections are associated with signifi cant morbidity and mortality and therefore they represent a serious health problem. All human IAV strains are originally derived from avian IAVs, which, aft er their adaptation to humans, can spread in the human population and cause pandemics with more or less severe course of the disease. Presently, however, the potential of avian IAV to infect humans and to cause the disease cannot be predicted. Many studies are therefore focused on factors infl uencing the virulence and pathogenicity of IAV viruses in a given host. Th e virus-host interaction starts by virus attachment via the envelope glycoprotein hemagglutinin (HA) to the receptors on the cell surface. In addition to receptor binding, HA mediates also the fusion of viral and endosomal membranes, which follows the virus endocytosis. Th e fusion potential of HA trimer, primed by proteolytic cleavage, is activated by low pH in endosomes, resulting in HA refolding into the fusion-active form. Th e HA conformation change is predetermined by its 3-D structure, is pH-dependent, irreversible and strain-specifi c. Th e process of fusion activation of IAV hemagglutinin is crucial for virus entry into the cell and for the ability of the virus to replicate in the host. Here we discuss the known data about the characteristics of fusion activation of HA in relation to IAV virulence and pathogenicity.Keywords: infl uenza A viruses; pH optimum of fusion; IAV virulence and pathogenicity; HA conformation change; IAV interspecies transmission; adaptation changes * Corresponding author. E-mail: viruevar@savba.sk; phone: 421-2-59302427. Abbreviations: HA = hemagglutinin; HA0 = HA precursor; HA1 = heavy chain of HA; HA2 = light chain of HA; HPAI = highly pathogenic avian infl uenza; IAV(s) = infl uenza A virus(es); LPAI = low pathogenic avian infl uenza; M1 protein = matrix protein; mRNA = messenger RNA; NA = neuraminidase; NEP protein = nuclear export protein; NS1 protein = nonstructural protein 1; PA = polymerase acidic protein; PB1 = polymerase basic protein 1; PB2 = polymerase basic protein 2; RBS = receptor binding site; RNA = ribonucleic acid; RNP = ribonucleoprotein; SA = sialic acid; vRNA = viral RNA Content: 1. Introduction 2. Structure and function of hemagglutinin 2.1 Receptor binding activity and IAV host tropism 2.2 Fusion activity and structural rearrangements of HA during the membrane fusion 3. Th e HA cleavability by host proteases and HA fusion activation pH as factors of IAV virulence and pathogenicity 3.1 Cleavage activation of HA as a determinant of IAV pathogenicity 3.2 Fusion activation pH as a determinant of IAV virulence 4. Th e role of fusion activation pH and stability of HA in the adaptation of IAV to the new host 5. Other viral proteins infl uencing the IAV virulence 6. Conclusion

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Influenza HA Subtypes Demonstrate Divergent Phenotypes for Cleavage Activation and pH of Fusion: Implications for Host Range and Adaptation

Cited by 186 publications

References 79 publications

Molecular requirements for a pandemic influenza virus: An acid-stable hemagglutinin protein

Molecular requirements for a pandemic influenza virus: An acid-stable hemagglutinin protein

Intermonomer Interactions in Hemagglutinin Subunits HA1 and HA2 Affecting Hemagglutinin Stability and Influenza Virus Infectivity

The role of fusion activity of influenza A viruses in their biological properties

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