A conserved histidine in Group-1 influenza subtype hemagglutinin proteins is essential for membrane fusion activity

Trost, Jessica F.; Wang, Wei; Liang, Bo; Galloway, Summer E.; Agbogu, Evangeline; Byrd-Leotis, Lauren; Steinhauer, David A.

doi:10.1016/j.virol.2019.08.005

Cited by 11 publications

(9 citation statements)

References 52 publications

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“…HA stability and the pH values that trigger conformational transformation vary among strains, and few mutations have been identified with a broad cross-subtype-stabilizing effect (27)(28)(29)(30). pH-sensitive regions that initiate the HA's large conformational changes have been previously described (14,15,21,(30)(31)(32)(33). In this study, we targeted the regions involved in early structural rearrangements to stabilize the HA trimers.…”

Section: Discussionmentioning

confidence: 99%

Universal stabilization of the influenza hemagglutinin by structure-based redesign of the pH switch regions

Milder

Jongeneelen

Ritschel

et al. 2022

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

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For an efficacious vaccine immunogen, influenza hemagglutinin (HA) needs to maintain a stable quaternary structure, which is contrary to the inherently dynamic and metastable nature of class I fusion proteins. In this study, we stabilized HA with three substitutions within its pH-sensitive regions where the refolding starts. An X-ray structure reveals how these substitutions stabilize the intersubunit β-sheet in the base and form an interprotomeric aliphatic layer across the stem while the native prefusion HA fold is retained. The identification of the stabilizing substitutions increases our understanding of how the pH sensitivity is structurally accomplished in HA and possibly other pH-sensitive class I fusion proteins. Our stabilization approach in combination with the occasional back mutation of rare amino acids to consensus results in well-expressing stable trimeric HAs. This repair and stabilization approach, which proves broadly applicable to all tested influenza A HAs of group 1 and 2, will improve the developability of influenza vaccines based on different types of platforms and formats and can potentially improve efficacy.

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Section: Discussionmentioning

confidence: 99%

Universal stabilization of the influenza hemagglutinin by structure-based redesign of the pH switch regions

Milder

Jongeneelen

Ritschel

et al. 2022

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

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“…The observed increase in viral receptor binding with the introduction of HA N129D suggests the following model. The prefusion conformation of HA proteins carrying bnAb escape mutations in the stem domain is destabilized, such that unfolding to the postfusion conformation is more likely to occur prematurely ( 18 , 31 , 45 ). This destabilization may in turn increase the fraction of HA protomers on a virion that are unable to mediate receptor binding, lowering the avidity of virion binding to cells.…”

Section: Discussionmentioning

confidence: 99%

“…Generally, antibodies to the stem are harder to elicit but have greater breadth than head-binding antibodies, neutralizing a broader range of IAVs ( 6 , 13 – 17 ). In addition, the stem region is thought to be inherently less permissive to viral escape because it is essential to stabilize the HA trimeric structure and to drive viral fusion through HA conformational change ( 18 , 19 ). Therefore, the stem has been regarded as a promising target for universal vaccines and antiviral therapeutics ( 7 ).…”

mentioning

confidence: 99%

Epistasis reduces fitness costs of influenza A virus escape from stem-binding antibodies

Lee

Raghunathan

Cáceres

et al. 2023

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

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The hemagglutinin (HA) stem region is a major target of universal influenza vaccine efforts owing to the presence of highly conserved epitopes across multiple influenza A virus (IAV) strains and subtypes. To explore the potential impact of vaccine-induced immunity targeting the HA stem, we examined the fitness effects of viral escape from stem-binding broadly neutralizing antibodies (stem-bnAbs). Recombinant viruses containing each individual antibody escape substitution showed diminished replication compared to wild-type virus, indicating that stem-bnAb escape incurred fitness costs. A second-site mutation in the HA head domain (N129D; H1 numbering) reduced the fitness effects observed in primary cell cultures and likely enabled the selection of escape mutations. Functionally, this putative permissive mutation increased HA avidity for its receptor. These results suggest a mechanism of epistasis in IAV, wherein modulating the efficiency of attachment eases evolutionary constraints imposed by the requirement for membrane fusion. Taken together, the data indicate that viral escape from stem-bnAbs is costly but highlights the potential for epistatic interactions to enable evolution within the functionally constrained HA stem domain.

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“…Generally, antibodies to the stem are harder to elicit but have greater breadth than head binding antibodies, neutralizing a broader range of IAVs 6, 14, 15, 16, 17 . In addition, the stem region is thought to be inherently less permissive to viral escape because it is essential to stabilize the HA trimeric structure and to drive viral fusion through HA conformational change 18, 19 . Therefore, the stem has been regarded as a promising target for universal vaccines and anti-viral therapeutics 7 .…”

Section: Introductionmentioning

confidence: 99%

Epistasis reduces fitness costs of influenza A virus escape from stem-binding antibodies

Lee

Cáceres

Geiger

et al. 2022

Preprint

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The hemagglutinin (HA) stem region is a major target of universal influenza vaccine efforts owing to the presence of highly conserved epitopes across multiple influenza A virus strains and subtypes. To explore the potential impact of vaccine-induced immunity targeting the HA stem, we examined the fitness effects of viral escape from stem-binding broadly neutralizing antibodies (stem-bnAbs). Recombinant viruses containing each individual antibody escape substitution showed diminished replication compared to wild-type virus, indicating that stem-bnAb escape incurred fitness costs. A second-site mutation in the HA head domain (N133D) reduced the fitness effects observed in primary cell cultures and likely enabled the selection of escape mutations. This putative permissive mutation was not, however, sufficient to ease fitness costs in a ferret transmission model. Taken together, these data suggest that viral escape from stem-bnAbs is costly but highlight the potential for epistatic interactions to enable evolution within the functionally constrained HA stem domain.

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A conserved histidine in Group-1 influenza subtype hemagglutinin proteins is essential for membrane fusion activity

Cited by 11 publications

References 52 publications

Universal stabilization of the influenza hemagglutinin by structure-based redesign of the pH switch regions

Universal stabilization of the influenza hemagglutinin by structure-based redesign of the pH switch regions

Epistasis reduces fitness costs of influenza A virus escape from stem-binding antibodies

Epistasis reduces fitness costs of influenza A virus escape from stem-binding antibodies

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