Viva la revolución: rethinking influenza A virus antigenic drift

Yewdell, Jonathan W.

doi:10.1016/j.coviro.2011.05.005

Cited by 37 publications

(38 citation statements)

References 55 publications

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“…Viruses that can tolerate a large number of mutations in their structural proteins, such as HIV-1, hepatitis C virus (HCV), influenza virus, and noroviruses, undergo rapid and substantial antigenic drift in the presence of immune pressure (4,(188)(189)(190)(191). This is evident in the yearly requirement for a reformulation of the seasonal influenza vaccine, as influenza viruses are extremely adept at acquiring antibody escape mutations (192,193). For viruses that cause…”

Section: Virus Evasion Of Antibody-mediated Neutralization Sequence Vmentioning

confidence: 99%

Deconstructing the Antiviral Neutralizing-Antibody Response: Implications for Vaccine Development and Immunity

VanBlargan

Goo

Pierson

2016

Microbiol Mol Biol Rev

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SUMMARY The antibody response plays a key role in protection against viral infections. While antiviral antibodies may reduce the viral burden via several mechanisms, the ability to directly inhibit (neutralize) infection of cells has been extensively studied. Eliciting a neutralizing-antibody response is a goal of many vaccine development programs and commonly correlates with protection from disease. Considerable insights into the mechanisms of neutralization have been gained from studies of monoclonal antibodies, yet the individual contributions and dynamics of the repertoire of circulating antibody specificities elicited by infection and vaccination are poorly understood on the functional and molecular levels. Neutralizing antibodies with the most protective functionalities may be a rare component of a polyclonal, pathogen-specific antibody response, further complicating efforts to identify the elements of a protective immune response. This review discusses advances in deconstructing polyclonal antibody responses to flavivirus infection or vaccination. Our discussions draw comparisons to HIV-1, a virus with a distinct structure and replication cycle for which the antibody response has been extensively investigated. Progress toward deconstructing and understanding the components of polyclonal antibody responses identifies new targets and challenges for vaccination strategies.

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Section: Virus Evasion Of Antibody-mediated Neutralization Sequence Vmentioning

confidence: 99%

Deconstructing the Antiviral Neutralizing-Antibody Response: Implications for Vaccine Development and Immunity

VanBlargan

Goo

Pierson

2016

Microbiol Mol Biol Rev

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“…Both the virus and the immune response to it have been extensively characterized at the molecular, immunological and epidemiological levels [1][2][3][4][5][6][7][8][9][10]. Current influenza vaccines focus on the generation of antibodies to the surface proteins haemagglutinin (HA) and, to a lesser extent, neuraminidase.…”

Section: Introductionmentioning

confidence: 99%

Masking of antigenic epitopes by antibodies shapes the humoral immune response to influenza

Zarnitsyna

Ellebedy

Davis

et al. 2015

Phil. Trans. R. Soc. B

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One contribution of 13 to a theme issue 'The dynamics of antibody repertoires'. The immune responses to influenza, a virus that exhibits strain variation, show complex dynamics where prior immunity shapes the response to the subsequent infecting strains. Original antigenic sin (OAS) describes the observation that antibodies to the first encountered influenza strain, specifically antibodies to the epitopes on the head of influenza's main surface glycoprotein, haemagglutinin (HA), dominate following infection with new drifted strains. OAS suggests that responses to the original strain are preferentially boosted. Recent studies also show limited boosting of the antibodies to conserved epitopes on the stem of HA, which are attractive targets for a 'universal vaccine'. We develop multi-epitope models to explore how pre-existing immunity modulates the immune response to new strains following immunization. Our models suggest that the masking of antigenic epitopes by antibodies may play an important role in describing the complex dynamics of OAS and limited boosting of antibodies to the stem of HA. Analysis of recently published data confirms model predictions for how pre-existing antibodies to an epitope on HA decrease the magnitude of boosting of the antibody response to this epitope following immunization. We explore strategies for boosting of antibodies to conserved epitopes and generating broadly protective immunity to multiple strains.

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“…With increasing concern regarding the effectiveness of IAV vaccination and the possibility of generating vaccines that induce broadly neutralizing Abs (14), there is a renewed interest in understanding not only HA antigenicity but also HA immunogenicity. Since virtually all neutralizing Abs are conformation specific, a critical issue is the generation of epitopes during the progressive folding of HA.…”

mentioning

confidence: 99%

Influenza A Virus Hemagglutinin Trimerization Completes Monomer Folding and Antigenicity

Magadán

Khurana

Das

et al. 2013

J Virol

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c Influenza A virus (IAV) remains an important human pathogen largely because of antigenic drift, the rapid emergence of antibody escape mutants that precludes durable vaccination. The most potent neutralizing antibodies interact with cognate epitopes in the globular "head" domain of hemagglutinin (HA), a homotrimeric glycoprotein. The H1 HA possesses five distinct regions defined by a large number of mouse monoclonal antibodies (MAbs), i.e., Ca1, Ca2, Cb, Sa, and Sb. Ca1-Ca2 sites require HA trimerization to attain full antigenicity, consistent with their locations on opposite sides of the trimer interface. Here, we show that full antigenicity of Cb and Sa sites also requires HA trimerization, as revealed by immunofluorescence microscopy of IAVinfected cells and biochemically by pulse-chase radiolabeling experiments. Surprisingly, epitope antigenicity acquired by HA trimerization persists following acid triggering of the globular domains dissociation and even after proteolytic release of monomeric heads from acid-treated HA. Thus, the requirement for HA trimerization by trimer-specific MAbs mapping to the Ca, Cb, and Sa sites is not dependent upon the bridging of adjacent monomers in the native HA trimer. Rather, complete antigenicity of HA (and, by inference, immunogenicity) requires a final folding step that accompanies its trimerization. Once this conformational change occurs, HA trimers themselves would not necessarily be required to induce a highly diverse neutralizing response to epitopes in the globular domain.T he influenza A virus (IAV) hemagglutinin (HA) glycoprotein attaches virions to target cells by binding terminal sialic acid residues on cell surface glycans (1, 2). As a prototypical homotrimeric type I integral membrane protein, HA is synthesized in the endoplasmic reticulum (ER) of infected cells and transported through the Golgi complex (GC) to the plasma membrane (PM), where it is incorporated into budding virions. A variable number (depending on the strain) of N-linked oligosaccharides are added cotranslationally as HA is extruded into the ER through the translocon and subsequently trimmed and modified extensively during HA transport to the cell surface. In addition, the cytoplasmic COOH terminus of HA is palmitoylated during its intracellular transport, likely in an early GC compartment (3).HA folding begins cotranslationally, as shown by the acquisition of intrachain disulfide bonds and by the binding of monoclonal antibodies (MAbs) specific for discontinuous epitopes within HA to nascent chains (4). Initial folding of HA monomers is likely completed shortly after chain termination (within 1 or 2 min), whereas HA trimerization occurs with a half-life of ϳ5 min (5, 6). The localization of the later process appears to be strain (and perhaps subtype) specific, with prototype H2 (7) and H3 (8) HAs trimerizing in the ER while the A/Puerto Rico/8/34 (PR8) H1 HA trimerizes in either the ER-Golgi intermediate compartment or the cis-GC (3, 6).HA is of great medical importance by virtue of its recog...

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Viva la revolución: rethinking influenza A virus antigenic drift

Cited by 37 publications

References 55 publications

Deconstructing the Antiviral Neutralizing-Antibody Response: Implications for Vaccine Development and Immunity

Deconstructing the Antiviral Neutralizing-Antibody Response: Implications for Vaccine Development and Immunity

Masking of antigenic epitopes by antibodies shapes the humoral immune response to influenza

Influenza A Virus Hemagglutinin Trimerization Completes Monomer Folding and Antigenicity

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