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Fitness Costs Limit Influenza a Virus Hemagglutinin Glycosylation Fitness costs limit influenza A virus hemagglutinin PNAS PLUS glycosylation as an immune evasion strategy Suman R. Dasa,b,1, Scott E. Hensleya,2, Alexandre Davida, Loren Schmidta, James S. Gibbsa, Pere Puigbòc, William L. Incea, Jack R. Benninka, and Jonathan W. Yewdella,3 aLaboratory of Viral Diseases, National Institute of Allergy and Infectious Disease, National Institutes of Health, Bethesda, MD 20892; bEmory Vaccine Center, Emory University, Atlanta, GA 30322; and cNational Center for Biotechnology Information, National Library of Medicine, National Institutes of Health, Bethesda, MD 20894 AUTHOR SUMMARY Influenza A virus remains an acid substitutions distributed important human pathogen among the four antigenic sites largely because of its ability to recognized by various mono- evade antibodies that neutralize clonal antibodies, indicating viral infectivity. The virus conserved antigenicity among escapes neutralization by alter- the mutants for this mAb (2). ing the target of these anti- Third and highly ironically, bodies, the HA glycoprotein, in escape mutants selected with a process known as antigenic H28-A2 show reduced binding drift. HA attaches the virus to to a remarkably large frac- specific molecules (terminal tion of other monoclonal anti- sialic acid residues) on target bodies (71%) that recognize cells to initiate the infectious one (or a combination) of the cycle. Antibodies that interact four antigenic sites in the glob- with the globular structure ular domain. of the HA protein physically Sequencing of two H28-A2 block virus attachment or the egg-generated escape mutants subsequent HA-mediated (OV1 and OV2) immediately fusion of viral and cellular revealed that their low fre- membranes, thereby neutraliz- quency and high degree of ing viral infectivity. Antigenic escape was because of a com- Fig. P1. Footprint of H28-A2 binding. Alterations in residues that drift results from the accumula- mon mutation (K144N) that reduce H28-A2 binding (225, 193, and 144) or abrogate it because of N tion of amino acid substitutions glycosylation (144 and 131) are shown in red. generated a potential -linked in the globular domain that re- glycosylation site at position duce binding to neutralizing 144 in the protein’s amino acid antibodies. sequence. Importantly, both OV1 and OV2 had an additional Hyperglycosylation, or the attachment of numerous sugar mutation, encoding either D225G or N193K (Fig. P1). Similar polymers to a protein, provides an alternative strategy that some selection in Madin Darby canine kidney (MDCK) cells also viruses (e.g., HIV) use to evade detection by antibodies, because generated an escape mutant (OV3) at an extremely low fre- the large size of these oligosaccharides can sterically prevent quency, with two mutations encoding a common substitution the antibody from accessing the particular amino acids that (K144N) accompanied by a different, less common sub- it recognizes. stitution (P186S). Interestingly, although the H3 HA viral subtype has gradually Unlike currently circulating seasonal H1N1 viruses, PR8 lacks gained glycosylation sites in the globular region (but still much glycosylation sites in the HA globular head. Residue 144 is lo- less than HIV gp160), the H1 HA subtype circulating for a sim- cated on the solvent-exposed surface of the head, where it can ilar period in a similarly large population has acquired far fewer easily accommodate the addition of an oligosaccharide (Fig. P1). sites. Moreover, the H2 HA subtype during its 10-y evolution To validate glycosylation at the introduced glycosylation site, we MICROBIOLOGY in humans maintained only a single glycosylation site in the purified WT PR8, OV1, OV2, and OV3 and the single escape globular domain. The limited accumulation of glycosylation sites mutants with identical alterations to the second site mutations in influenza HA suggests a high evolutionary fitness cost. observed in the OV variants (D225G, N193K, and P186S). The Here, we provide compelling evidence for this conclusion by studying the ability of the prototypical H1 strain A/PR/8/1934 (PR8) to escape neutralization by a unique monoclonal anti- Author contributions: S.R.D., J.R.B., and J.W.Y. designed research; S.R.D., S.E.H., A.D., L.S., body designated H28-A2, which selects viruses that escape J.S.G., P.P., W.L.I., and J.W.Y. performed research; S.R.D. contributed new reagents/ neutralization only through the acquisition of an additional analytic tools; S.R.D., S.E.H., A.D., L.S., J.S.G., P.P., W.L.I., J.R.B., and J.W.Y. analyzed data; and S.R.D., J.R.B., and J.W.Y. wrote the paper. N-linked glycosylation site in the globular domain of HA. fl Of hundreds of characterized monoclonal antibodies that The authors declare no con ict of interest. specifically recognize PR8 HA, H28-A2 exhibits a number of This article is a PNAS Direct Submission. 1 unique properties. First, its presence selects for escape Present address: Infectious Diseases Group, J. Craig Venter Institute, Rockville, MD 20852. mutants—variants of the virus that are able to survive H28-A2 2Present address: Immunology Program, The Wistar Institute, Philadelphia, PA 19130. neutralization—at a frequency expected for a double simulta- 3To whom correspondence should be addressed. E-mail: [email protected]. −9 neous mutation (<10 ) (1). Second, H28-A2 shows little change See full research article on page E1417 of www.pnas.org. in binding strength to a set of >40 escape mutants with amino Cite this Author Summary as: PNAS 10.1073/pnas.1108754108. www.pnas.org/cgi/doi/10.1073/pnas.1108754108 PNAS | December 20, 2011 | vol. 108 | no. 51 | 20289–20290 Downloaded by guest on September 27, 2021 results clearly showed that the oligosaccharide attachment site predicted to be glycosylated at position 131. All 98 of these generated by the more common substitution is used. isolates also possess the P186S substitution, which increases re- Both the bulkiness of an N-linked oligosaccharide and the ceptor avidity and has minimal effects on HA antigenicity (4). central location of the mutated K144N residue amid the anti- Taken together, these findings support the conclusion that gly- genic sites in the globular domain (Fig. P1) could explain the cosylation at position 144 incurs enormous fitness costs that have dramatically altered antigenicity of H28-A2 escape mutants. yet to be surmounted in H1 evolution. Although glycosylation Because the second site mutations in the escape mutants are at position 131 is disfavored, it can exist in circulating strains with likely not needed for evading antibody neutralization, these compensatory mutations that restore HA receptor avidity. mutations may allow the virus to compensate for the functional Given the dramatic effect of position 144 glycosylation on HA fi de cits caused by glycosylation at the common substitution site antigenicity, we might expect that H28-A2 escape mutants show (residue 144). robust escape from Ab-based inhibition; however, hemaggluti- fi We con rmed this hypothesis by showing that compensatory nation inhibition assays showed that glycosylation had either mutations appeared as soon as viruses engineered to contain the a minor positive effect on escape or remarkably, the opposite K144N substitution were expanded in eggs or MDCK cells. Se- effect on escape. quencing of viruses grown in egg revealed D225G or I194L We extended these findings to an in vivo infection model by substitutions, whereas viruses grown in MDCK cells harbored immunizing mice with PR8, challenging them with WT, P186S, three types of substitutions: alterations of N144 removing the or K144N, P186S viruses, and measuring viral lung titers 2 d after glycosylation site, compensatory changes (P186S or G156E), and most remarkably, single or double substitutions in neuramini- infection. In naïve mice, all three viruses replicated to similar dase, another viral protein that acts to remove the sialic recep- titers. However, vaccination completely prevented replication of tors bound by HA. The latter result confirmed our recent finding the WT virus but only reduced the replication of P186S by 10- that antigenic escape mutants in HA that limit viral fitness can fold, similar to what we previously reported (5). By contrast, increase fitness by epistatic amino acid substitutions in neur- mice were completely protected against K144N, P186S virus aminidase (3). infection, despite the enormous antigenic escape associated with Furthermore, we confirmed the compensatory nature of sec- glycosylation at position 144. ond site substitutions (D225G, N193K, and P186S) by using These findings suggest that receptor avidity can be a more H28-A2 in the MDCK cell system to select escape mutants from important factor than antigenicity in escaping from neutralizing PR8 mutants with substitutions in these defined compensatory antibodies. This finding limits the use of glycosylation as a means sites. Variant frequencies occurred within the range typical of of HA immune escape, because it reduces receptor avidity. single point mutants, with a lower frequency of mutants with Understanding the features of antibodies that resist antigenic N193K likely because of the poor adaptation of these double drift is of practical importance in devising vaccines for viruses mutants to MDCK cells. Moreover, sequencing revealed the like influenza A virus and HIV, where antigenic variation greatly expected but also a surprise: mutants obtained from N193K or impacts vaccine effectiveness. The low frequency of H28-A2 P186S stocks possessed the expected K144N substitution, escape mutants, in conjunction with their special nature in gen- whereas only one-half of D225G mutants possessed this sub- erating a glycosylation site, conclusively indicates that HA is stitution. Remarkably, the other one-half possessed an N133T incapable of generating viable mutants with single amino acid substitution, now creating a glycosylation site on the solvent- substitutions that enable escape from H28-A2. accessible surface close to residue 144 and the receptor binding Glycosylation at position 144 reduced HA receptor affinity, site (i.e., the cavity in the globular domain that binds to receptors consistent with the findings of prior studies documenting dele- on the target cell) (Fig.
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