Antigenic Structure of Flavivirus Proteins

doi:10.1016/S0065-3527(03)59005-4

Advances in Virus Research

Volume 59, 2003, Pages 141-175

https://doi.org/10.1016/S0065-3527(03)59005-4 Get rights and content

Abstract

The increased activity of Dengue virus in the tropical regions of the world and the recent movement of West Nile virus from the eastern to the western hemisphere emphasize the fact that vector-borne flaviviruses are medically important emerging infectious diseases. These facts warrant continued efforts to decode all facets of flavivirus immunology. This chapter reviews current understanding of the antigenic fine structure of flaviviral structural and nonstructural (NS) proteins and their involvement in B- and T-cell host responses. The virion structural glycoprotein E elicits both virus-neutralizing antibodies and antiviral T_H-cell responses. Consistent with the current hypothesis of the MHC class I pathway of protein processing, immunodominant flaviviral T_C-cell epitopes mainly reside on the NS proteins. To prepare effective and inexpensive subunit vaccines, we will need to continue to better understand these structure–function relationships of flavivirus proteins.

Introduction

Although our understanding of the antigenic structure of flaviviruses has continued to progress, largely due to the development and application of monoclonal antibodies (Mabs) to the process, the pace of new discoveries in this field has slowed over the past few years. The reason for this is not certain; however, the development of promising live-attenuated virus vaccine candidates for dengue (DEN) virus and other medically important flaviviruses is certainly a contributing factor. The recent movement of West Nile (WN) virus from the eastern to the western hemisphere emphasizes the fact that vector-borne flaviviruses still “have some tricks up their sleeves,” and this fact alone warrants continued efforts to better understand all facets of flavivirus immunology (Craven 2001, Gubler 2000, Lanciotti 1999, Marfin 2001, Nash 2001, Petersen 2001). To this end, our current understanding of flavivirus B- and T-cell responses has been the subject of a number of fairly recent reviews to which the reader is also referred (Heinz 1986, Heinz 1990, Roehrig 1997).

Section snippets

Classical flavivirus serology

Since the identification of flaviviruses as serologically distinct entities (first known as group B arboviruses), a number of their antigenic properties have been identified. The family Flaviviridae, genus Flavivirus, contains over 70 members, and all of these viruses have been shown to be antigenically related to some degree (Calisher 1988, Calisher 1989, De Madrid 1974). These antigenic relationships serve as the backbone for the taxonomy and classification of flaviviruses as discussed

E-glycoprotein

The advent of Mab technology permitted dissection of the antigenic properties of proteins at a level never before imagined. In the 1980s, this technology blossomed as it was applied to a wide variety of flaviviruses, including WN (Besselaar 1988, Peiris 1982) tick-borne encephalitis (TBE) (Gaidamovich 1989, Heinz 1983b, Heinz 1984a, Stephenson 1984), yellow fever (YF) (Barrett 1989, Buckley 1985, Cammack 1986a, Cammack 1986b, Gould 1985, Gould 1989, Schlesinger 1983), St. Louis encephalitis

Helper T-Cell Epitopes

Studies in mouse models have determined that flavivirus structural proteins are important in eliciting an antiviral helper T-cell (T_h) response (Chaturvedi 1987, Kulkarni 1992). The virus specificity of this T_h-cell response can be serotype specific or virus cross-reactive (Rothman 1989, Uren 1987). An anti–DEN virus T_h-cell response can be detected as early as 2 weeks after immunization, can be stable for at least 12 weeks, and is still measurable at 1 year after immunization. When DEN

Conclusion

The current popular approach to flavivirus vaccine development is to construct full-length infectious cDNA virus clones and use them as substrates to produce chimeric flaviviruses or fully attenuated and stable viruses capable of eliciting a complete and long-lasting immunity. It is likely, however, that these vaccines will be expensive to produce, difficult to maintain because of requirements for a cold chain, and costly for the consumer. Many countries that would be targeted for DEN, JE, and

References (193)

S.C. Adams et al.
Glycosylation and antigenic variation among Kunjin virus isolates
Virology
(1995)
A.D. Barrett et al.
Examination of the envelope glycoprotein of yellow fever vaccine viruses with monoclonal antibodies
Vaccine
(1989)
D.W. Beasley et al.
Epitopes on the dengue 1 virus envelope protein recognized by neutralizing IgM monoclonal antibodies
Virology
(2001)
N. Cammack et al.
Antigenic analysis of yellow fever virus glycoproteins: Use of monoclonal antibodies in enzyme-linked immunosorbent assays
J. Virol. Methods
(1986)
N. Cammack et al.
Topographical analysis of epitope relationships on the envelope glycoprotein of yellow fever 17D vaccine and the wild type Asibi parent virus
Virology
(1986)
D. Cecilia et al.
Nucleotide changes responsible for loss of neuroinvasiveness in Japanese encephalitis virus neutralization-resistant mutants
Virology
(1991)
J. Corver et al.
Membrane fusion activity of tick-borne encephalitis virus and recombinant subviral particles in a liposomal model system
Virology
(2000)
S. Green et al.
Recognition of dengue virus NS1-NS2a proteins by human CD4⁺ cytotoxic T lymphocyte clones
Virology
(1997)
F. Guirakhoo et al.
The Murray Valley encephalitis virus prM protein confers acid resistance to virus particles and alters the expression of epitopes within the R2 domain of E glycoprotein
Virology
(1992)
F. Guirakhoo et al.
Epitope model of tick-borne encephalitis virus envelope glycoprotein E: Analysis of structural properties, role of carbohydrate side chain, and conformational changes occurring at acidic pH
Virology
(1989)

H. Hasegawa et al.

Mutations in the envelope protein of Japanese encephalitis virus affect entry into cultured cells and virulence in mice

Virology

(1992)

F.X. Heinz

Epitope mapping of flavivirus glycoproteins

Adv. Virus. Res.

(1986)

F.X. Heinz et al.

Location of immunodominant antigenic determinants on fragments of the tick-borne encephalitis virus glycoprotein: Evidence for two different mechanisms by which antibodies mediate neutralization and hemagglutination inhibition

Virology

(1983)

F.X. Heinz et al.

A topological and functional model of epitopes on the structural glycoprotein of tick-borne encephalitis virus defined by monoclonal antibodies

Virology

(1983)

F.X. Heinz et al.

Antibody-induced conformational changes result in enhanced avidity of antibodies to different antigenic sites on the tick-borne encephalitis virus glycoprotein

Virology

(1984)

L.C. Iacono-Connors et al.

Characterization of Langat virus antigenic determinants defined by monoclonal antibodies to E, NS1 and preM and identification of a protective, nonneutralizing preM-specific monoclonal antibody

Virus Res

(1996)

G. Kuno et al.

Antigen capture ELISA for the identification of dengue viruses

J. Virol. Methods

(1985)

I. Kurane et al.

Definition of an epitope on NS3 recognized by human CD4⁺ cytotoxic T lymphocyte clones cross-reactive for dengue virus types 2, 3, and 4

Virology

(1998)

J.G. Aaskov et al.

Serologically defined linear epitopes in the envelope protein of dengue 2 (Jamaica strain 1409)

Arch. Virol.

(1989)

J.G. Aaskov et al.

Failure of a dengue 1 sub-unit vaccine to protect mice against a lethal dengue virus infection

Am. J. Trop. Med. Hyg.

(1988)

H. Aihara et al.

Establishment and characterization of Japanese encephalitis virus-specific, human CD4(+) T-cell clones: Flavivirus cross-reactivity, protein recognition, and cytotoxic activity

J. Virol.

(1998)

S.L. Allison et al.

Mutational evidence for an internal fusion peptide in flavivirus envelope protein E

J. Virol.

(2001)

T.G. Besselaar et al.

Antigenic analysis of West Nile virus strains using monoclonal antibodies

Arch. Virol.

(1988)

S. Bhardwaj et al.

Biophysical characterization and vector-specific antagonist activity of domain III of the tick-borne flavivirus envelope protein

J. Virol.

(2001)

M.W. Brandriss et al.

Lethal 17D yellow fever encephalitis in mice: I. Passive protection by monoclonal antibodies to the envelope proteins of 17D yellow fever and dengue 2 viruses

J. Gen. Virol.

(1986)

A. Buckley et al.

Monoclonal antibodies identify the NS5 yellow fever virus non-structural protein in the nuclei of infected cells

J. Gen. Virol.

(1992)

A. Buckley et al.

Neutralization of yellow fever virus studied using monoclonal and polyclonal antibodies

J. Gen. Virol.

(1985)

J.F. Bukowski et al.

Dengue virus-specific cross-reactive CD8⁺ human cytotoxic T lymphocytes

J. Virol.

(1989)

R. Bulich et al.

Nuclear localization of dengue 2 virus core protein detected with monoclonal antibodies

J. Gen. Virol.

(1992)

S. Butrapet et al.

Neutralizing mechanism of a monoclonal antibody against Japanese encephalitis virus glycoprotein E

Am. J. Trop. Med. Hyg.

(1998)

C.H. Calisher

Antigenic classification and taxonomy of flaviviruses (family Flaviviridae) emphasizing a universal system for the taxonomy of viruses causing tick-borne encephalitis

Acta Virol.

(1988)

C.H. Calisher et al.

Antigenic relationships between flaviviruses as determined by cross-neutralization tests with polyclonal antisera

J. Gen. Virol.

(1989)

R.D. Cardiff et al.

Immunological and biophysical separation of dengue-2 antigens

J. Virol.

(1971)

D. Cecilia et al.

Epitope mapping of Japanese encephalitis virus envelope protein using monoclonal antibodies against an Indian strain

J. Gen. Virol.

(1988)

U.C. Chaturvedi et al.

Dengue virus-induced helper T cells

Indian J. Med. Res.

(1987)

R.B. Craven et al.

West Nile virus

JAMA

(2001)

W.D. Crill et al.

Monoclonal antibodies that bind to domain III of dengue virus E glycoprotein are the most efficient blockers of virus adsorption to Vero cells

J. Virol.

(2001)

A.T. De Madrid et al.

The flaviviruses (group B arboviruses): A cross-neutralization study

J. Gen. Virol.

(1974)

T. Dharakul et al.

Dengue virus-specific memory T cell responses in human volunteers receiving a live attenuated dengue virus type 2 candidate vaccine

J. Infect. Dis.

(1994)

D. Dittmar et al.

Monoclonal antibodies specific for dengue virus type 3

J. Clin. Microbiol.

(1980)

K.H. Eckels et al.

Virion and soluble antigens of Japanese encephalitis virus

Infect. Immun.

(1975)

A.K. Falconar et al.

Production of dimer-specific and dengue virus group cross-reactive mouse monoclonal antibodies to the dengue 2 virus nonstructural glycoprotein NS1

J. Gen. Virol.

(1991)

A.K. Falconar et al.

Precise location of sequential dengue virus subcomplex and complex B cell epitopes on the nonstructural-1 glycoprotein

Arch. Virol.

(1994)

W.A. Falkler et al.

Human antibody to dengue soluble complement-fixing (SCF) antigens

J. Immunol.

(1973)

S.J. Gagnon et al.

Identification of two epitopes on the dengue 4 virus capsid protein recognized by a serotype-specific and a panel of serotype-cross-reactive human CD4⁺ cytotoxic T-lymphocyte clones

J. Virol.

(1996)

S.I. Gaidamovich et al.

Antigenic analysis of tick-borne encephalitis virus group using monoclonal antibodies and immunofluorescence

Vopr. Virusol.

(1989)

G.F. Gao et al.

Identification of naturally occurring monoclonal antibody escape variants of louping ill virus

J. Gen. Virol.

(1994)

G. Garcia et al.

Recognition of synthetic oligopeptides from nonstructural proteins NS1 and NS3 of dengue-4 virus by sera from dengue virus-infected children

Am. J. Trop. Med. Hyg.

(1997)

M.K. Gentry et al.

Identification of distinct antigenic determinants on dengue-2 virus using monoclonal antibodies

Am. J. Trop. Med. Hyg.

(1982)

S.N. Ghosh et al.

Epitope analysis of strains of Japanese encephalitis virus by monoclonal antibodies

Indian J. Med. Res.

(1989)

Cited by (243)

Longitudinal serum profiling in Dengue fever patients with different severities by using multiplex flavivirus antigen microarrays
2024, Microchemical Journal
Dengue fever is one of the most common arbovirus-infected diseases and typically progresses through the febrile, critical, and convalescent phases. While most Dengue Fever patients have mild symptoms, a few develop severe symptoms due to hyperimmune responses. However, the role of the humoral responses during the Dengue fever progression, especially in severe cases, is still unclear. Here, we developed multiplex Flavivirus Antigen Microarrays (FAMs) for profiling antibody specificities in different infection phases and Dengue fever severities. The FAMs comprised 17 nonstructural and envelope proteins from Flaviviruses that frequently infect humans, e.g., 4 serotypes of Dengue viruses, Zika virus, Japanese encephalitis virus, West Nile virus, Yellow fever virus, and Tick-borne encephalitis virus. We collected serum samples from Dengue fever patients with different degrees of severity, including mild (n = 17), hospitalized non-severe (n = 21), and severe (n = 19), during febrile (Day < 7) and convalescent (Day > 7) phases. We simultaneously profiled the serum IgG and IgM against multiple antigens on the FAMs to demonstrate the immunological signatures in Dengue fever patients with different severities and two infection stages. Compared to febrile phase, the convalescent phase of mild but not hospitalized cases exhibiting evoked Dengue-specific IgM. In IgG profiling, the convalescent phase showed generally higher immune responses compared to febrile phase. Moreover, in the febrile phase, the hospitalized patients displayed higher IgG levels against 4 serotypes of Dengue viruses, Zika virus, and West Nile virus compared to mild patients, suggesting early and strong humoral responses. This study provides a valuable tool for monitoring antibody specificities and advances our understanding of humoral responses along with Dengue fever severities.
Novel mutations in structural proteins of dengue virus genomes
2023, Journal of Infection and Public Health
Genomic characterization of the dengue virus (DENV) is useful for understanding its molecular evolution, transmission, pathogenicity and infectivity. The DENV genomic RNA encodes three structural proteins, capsid (C) envelope (E) and membrane (M) proteins mediating viral entry and assembly during host infection. The current study aims to explore the DENV serotypes and mutations in the E and M proteins.
Twenty-three samples of DENV-positive patients were processed and selected for whole genome sequencing (WGS) from the Punjab Province of Pakistan.
Among the 23 WGS, 19 samples showed numerous mutations (BioProject ID PRJNA943555). DENV1 and DENV2 are the most prevalent serotypes. A total of 179 mutations were detected in the E protein, in which K203E, T88A, I114L, and I293T are novel. The I270L, T272A, S273L, and T277A were found in the “kl” β-hairpin (aa 270–279). The M protein harbors 74 mutations, of which 24 were novel. Three prominent complementary regions in the prM and E protein complex formations include R6, E46, D47, D63, and D65 on ‘pr’ peptide, and E84, K64, and H244, K247 on E, remain conserved except R6C. To our knowledge, it is the first comprehensive study of mutations in structural proteins.
Genomic epidemiology is critical for analyzing emerging mutations and designing new policies therapeutic efforts for future outbreaks.
Activity of domain III-specific antibodies in early convalescence: A case study
2023, Virology
The Dengue virus complex (DENV), formed by four serotypes, constitutes the most important arbovirus affecting humans. The structural domain III of their envelope protein (DIII) elicits strongly neutralizing serotype-specific antibodies. Contrasting results have been obtained regarding their role in the serum neutralizing activity of infected patients. We used a DENV immune serum from a secondary infection to examine the impact of characterizing the anti-DIII antibody response after affinity purification with recombinant DIII proteins to eliminate potential interferences from the interactions with human plasma proteins and other anti-DENV antibodies. Total anti-DENV IgG repertoire and anti-DIIIE antibodies were compared in functionality. In early convalescence, reactivity of anti-DIII antibodies is serotype specific and exhibits the strongest reactivity with infecting serotypes. Purification of anti-DIII antibodies emphasizes the reactivity profile as compared to total IgG fraction and serum. Serotype-specificity of the virus neutralization activity correlated with the apparent kD of the binding to recombinant DIIIs.
Dengue virus infection – a review of pathogenesis, vaccines, diagnosis and therapy
2023, Virus Research
The transmission of dengue virus (DENV) from an infected Aedes mosquito to a human, causes illness ranging from mild dengue fever to fatal dengue shock syndrome. The similar conserved structure and sequence among distinct DENV serotypes or different flaviviruses has resulted in the occurrence of cross reaction followed by antibody-dependent enhancement (ADE). Thus far, the vaccine which can provide effective protection against infection by different DENV serotypes remains the biggest hurdle to overcome. Therefore, deep investigation is crucial for the potent and effective therapeutic drugs development. In addition, the cross-reactivity of flaviviruses that leads to false diagnosis in clinical settings could result to delay proper intervention management. Thus, the accurate diagnostic with high specificity and sensitivity is highly required to provide prompt diagnosis in respect to render early treatment for DENV infected individuals. In this review, the recent development of neutralizing antibodies, antiviral agents, and vaccine candidates in therapeutic platform for DENV infection will be discussed. Moreover, the discovery of antigenic cryptic epitopes, principle of molecular mimicry, and application of single-chain or single-domain antibodies towards DENV will also be presented.
Modeling and complexity in dynamics of T-cells and cytokines in dengue fever based on antiviral treatment
2021, Chaos, Solitons and Fractals
Dengue fever is one of the most common vector-borne diseases spreading in tropical and subtropical regions of the world. It is commonly known as break-bone fever which has illness caused by dengue virus Aedes aegypti and Aedes albopictus mosquitoes. This paper presents a mathematical model for the dynamics of T-cells and cytokines in dengue infection based on antiviral treatment. We have classified the cell population into susceptible cell, infected cells, virus particles, T-cells and cytokines. Cytokines- a group of proteins play a very crucial role in elimination of dengue infection. We have considered death of cytokines during virus encounter. In earlier studies, only natural death rate of cytokines is considered. The stability analysis of the equilibrium points is discussed. If the reproduction number ( $R_{0}$ ) is less than 1, the endemic equilibrium point is stable and virus infection die out from the system and if reproduction umber is greater than 1, the endemic equilibrium point is unstable and virus infection persist in the system We also derived various key parameters which are responsible for extinction of virus from body. Numerical simulation has also been carried out to assess the effects of various key parameters on population.
Mapping of a unique epitope on domain III of the envelope protein of Tembusu virus
2021, Virus Research
We recently developed a Tembusu virus (TMUV)-specific monoclonal antibody (MAb) 12F11, which was found to recognize a long amino acid sequence between residues 8 and 77 of domain III of the envelope protein (EDIII). Here, the epitope recognized by MAb 12F11 was mapped using alanine substitutions combined with dissociation constant analysis. The findings, and prediction of tertiary structure of TMUV EDIII, showed that the MAb 12F11 epitope contained one critical residue and 13 peripheral residues. Moreover, the antigenic site was shown to span four loops (N-terminal region, AB, BC, and CD) and three β-strands (A, B, and D). The present work contributes to the understanding of antigenic structure of TMUV envelope protein.

View all citing articles on Scopus

View full text

Antigenic Structure of Flavivirus Proteins

Abstract

Introduction

Section snippets

Classical flavivirus serology

E-glycoprotein

Helper T-Cell Epitopes

Conclusion

Virology

Vaccine

Virology

J. Virol. Methods

Virology

Virology

Virology

Virology

Virology

Virology

Virology

Adv. Virus. Res.

Virology

Virology

Virology

Virus Res

J. Virol. Methods

Virology

Serologically defined linear epitopes in the envelope protein of dengue 2 (Jamaica strain 1409)

Arch. Virol.

Failure of a dengue 1 sub-unit vaccine to protect mice against a lethal dengue virus infection

Am. J. Trop. Med. Hyg.

Establishment and characterization of Japanese encephalitis virus-specific, human CD4(+) T-cell clones: Flavivirus cross-reactivity, protein recognition, and cytotoxic activity

J. Virol.

Mutational evidence for an internal fusion peptide in flavivirus envelope protein E

J. Virol.

Antigenic analysis of West Nile virus strains using monoclonal antibodies

Arch. Virol.

Biophysical characterization and vector-specific antagonist activity of domain III of the tick-borne flavivirus envelope protein

J. Virol.

Lethal 17D yellow fever encephalitis in mice: I. Passive protection by monoclonal antibodies to the envelope proteins of 17D yellow fever and dengue 2 viruses

J. Gen. Virol.

Monoclonal antibodies identify the NS5 yellow fever virus non-structural protein in the nuclei of infected cells

J. Gen. Virol.

Neutralization of yellow fever virus studied using monoclonal and polyclonal antibodies

J. Gen. Virol.

Dengue virus-specific cross-reactive CD8+ human cytotoxic T lymphocytes

J. Virol.

Nuclear localization of dengue 2 virus core protein detected with monoclonal antibodies

J. Gen. Virol.

Neutralizing mechanism of a monoclonal antibody against Japanese encephalitis virus glycoprotein E

Am. J. Trop. Med. Hyg.

Antigenic classification and taxonomy of flaviviruses (family Flaviviridae) emphasizing a universal system for the taxonomy of viruses causing tick-borne encephalitis

Acta Virol.

Antigenic relationships between flaviviruses as determined by cross-neutralization tests with polyclonal antisera

J. Gen. Virol.

Immunological and biophysical separation of dengue-2 antigens

J. Virol.

Epitope mapping of Japanese encephalitis virus envelope protein using monoclonal antibodies against an Indian strain

J. Gen. Virol.

Dengue virus-induced helper T cells

Indian J. Med. Res.

West Nile virus

JAMA

Monoclonal antibodies that bind to domain III of dengue virus E glycoprotein are the most efficient blockers of virus adsorption to Vero cells

J. Virol.

The flaviviruses (group B arboviruses): A cross-neutralization study

J. Gen. Virol.

Dengue virus-specific memory T cell responses in human volunteers receiving a live attenuated dengue virus type 2 candidate vaccine

J. Infect. Dis.

Monoclonal antibodies specific for dengue virus type 3

J. Clin. Microbiol.

Virion and soluble antigens of Japanese encephalitis virus

Infect. Immun.

Production of dimer-specific and dengue virus group cross-reactive mouse monoclonal antibodies to the dengue 2 virus nonstructural glycoprotein NS1

J. Gen. Virol.

Precise location of sequential dengue virus subcomplex and complex B cell epitopes on the nonstructural-1 glycoprotein

Arch. Virol.

Human antibody to dengue soluble complement-fixing (SCF) antigens

J. Immunol.

Identification of two epitopes on the dengue 4 virus capsid protein recognized by a serotype-specific and a panel of serotype-cross-reactive human CD4+ cytotoxic T-lymphocyte clones

J. Virol.

Dengue virus-specific cross-reactive CD8⁺ human cytotoxic T lymphocytes

Identification of two epitopes on the dengue 4 virus capsid protein recognized by a serotype-specific and a panel of serotype-cross-reactive human CD4⁺ cytotoxic T-lymphocyte clones