Viral apoptotic mimicry: an immune evasion strategy developed by the hepatitis B virus?

doi:10.1016/S1471-4906(03)00026-7

Trends in Immunology

Volume 24, Issue 3, March 2003, Pages 144-147

https://doi.org/10.1016/S1471-4906(03)00026-7 Get rights and content

Abstract

The co-existence of viruses and organisms for millions of years has influenced the evolution of both. Various viral strategies to enter a host and take over the control of cells to produce virus progeny have developed. Several antiviral (immune) responses have also been developed. The apoptotic death program is a conserved feature of eukaryotic cells. In multicellular organisms the binding and engulfment of apoptotic material is considered to be the end stage of the apoptotic process. Because of its importance, it seems probable that viruses have targeted this ancient removal system to suppress immune responses and to establish or maintain infection. The possibility that the hepatitis B virus has evolved such a mechanism, termed ‘viral apoptotic-like mimicry’, is presented here.

Section snippets

HBsAg has anti-inflammatory potential similar to APCEs

HBV is a non-cytopathogenic virus, which might explain why HBV infections often remain unnoticed. However, several studies have suggested a general modulation of antigen-presenting cells [APCs; monocytes, macrophages and dendritic cells (DCs)] in chronically infected patients. An altered balance of Th1 and Th2 responses [5] and defects in the antigen-presenting activity of DCs have been observed [6]. In comparison to peripheral-blood mononuclear cells (PBMCs) from healthy subjects, PBMCs from

HBsAg interacts with molecules that bind APCEs

Several cell membrane-bound receptors have been identified that recognize APCEs: the asialoglycoprotein receptor, class A and B scavenger receptors (SR-A and SR-BI), CD36, macrosialin or oxidized low-density lipoprotein (oxLDL) receptor (CD68), lectin-like oxLDL receptor-1 (LOX-1), ATP-binding cassette transporter 1 (ABC1), αvβ3 and αvβ5 vitronectin receptor, MER tyrosine kinase receptor [a member of the TAM (Tyro–Axl–Mer tyrosine kinase) receptor family, expressed on monocytes and tissues of

Are circulating complement–HBsAg complexes preventing adaptive immunity towards the viral envelope proteins?

A recent paper described the unexpected importance of complement and complement receptors (CR3 and CR4) in the uptake of circulating APCEs by splenic marginal zone DCs. Following the phagocytosis of complement-opsonized APCEs, decreased levels of proinflammatory cytokine secretion, without an effect on TGF-β secretion, was observed. This cytokine switch is thought to diminish antigen-driven T-cell stimulation by DCs that ingested APCEs and this might lead to immune unresponsiveness (peripheral

Concluding remarks

The evidence for the hypothesis of ‘viral apoptotic mimicry’ gathered here mainly comes from (older) studies that did not focus on viral evasion of immunity by the HBV. It is now hoped that this hypothesis results in renewed interest on the possible role of HBsAg in immune evasion. Of major importance is to determine the PL content of HBsAg, when freshly secreted by hepatocytes, and to determine if this content changes during circulation. If changes in PL content or oxidation of PLs occur, the

References (39)

P. Vanlandschoot
Recombinant HBsAg, an apoptotic-like lipoprotein, interferes with the LPS-induced phosphorylation of ERK-1/2 and JNK-1/2 in monocytes
Biochem. Biophys. Res. Commun.
(2002)
F. Gavilanes
Structure of hepatitis B surface antigen. Characterization of the lipid components and their association with the viral proteins
J. Biol. Chem.
(1982)
K. Balasubramanian
Immune clearance of phophatidylsreine-expressing cells by phagocytes. The role of β2-glycoprotein I in macrophage recognition
J. Biol. Chem.
(1997)
K. Balasubramanian et al.
Characterization of phosphatidylserine-dependent β2-glycoprotein I macrophage interactions. Implications for apoptotic-cell clearance by phagocytes
J. Biol. Chem.
(1998)
I. Stefas
Hepatitis B virus Dane particles bind to human plasma apolipoprotein H
Hepatology
(2001)
C.D. Gregory
CD14-dependent clearance of apoptotic cells: relevance to the immune system
Curr. Opin. Immunol.
(2000)
A.E. Morelli
Internalization of circulating apoptotic cells by splenic marginal-zone dendritic cells: dependence on complement receptors and effect on cytokine production
Blood
(2003)
W. Fiers
More than one way to die: apoptosis, necrosis and reactive oxygen damage
Oncogene
(1999)
D. Tortorella
Viral subversion of the immune system
Annu. Rev. Immunol.
(2000)
A. Alcami et al.
Viral mechanisms of immune evasion
Trends Microbiol.
(2000)

D.R. Milich

Immune response to the hepatitis B virus: infection, animal models, vaccination

Viral Hepatitis. Rev.

(1997)

B.D. Livingston

Altered helper T-lymphocyte function associated with chronic hepatitis B virus infection and its role in response to therapeutic vaccination in humans

J. Immunol.

(1999)

S.M. Akbar

Dendritic cells and chronic hepatitis virus carriers

Intervirology

(2001)

C. Jochum

Immunosuppressive function of hepatitis B antigens in vitro: role of endoribonuclease V as one potential trans inactivator for cytokines in macrophages and human hepatoma cells

J. Virol.

(1990)

P. Vanlandschoot

Hepatitis B surface antigen suppresses the activation of monocytes through interaction with a serum protein and a monocyte-specific receptor

J. Gen. Virol.

(2002)

V.A. Fadok

Macrophages that have ingested apoptotic cells in vitro inhibit proinflammatory cytokine production through autocrine/paracrine mechanisms involving TGF-β, PGE₂ and PAF

J. Clin. Invest.

(1998)

P.P. McDonald

Transcriptional and translational regulation of inflammatory mediator production by endogenous TGF-β in macrophages that have ingested apoptotic cells

J. Immunol.

(1999)

R.E. Voll

Immunosuppressive effects of apoptotic cells

Nature

(1997)

A. Byrne et al.

Lipopolysaccharide induces rapid production of IL-10 by monocytes in the presence of apoptotic neutrophils

J. Immunol.

(2002)

Cited by (57)

Apoptotic vesicles ameliorate lupus and arthritis via phosphatidylserine-mediated modulation of T cell receptor signaling
2023, Bioactive Materials
Mesenchymal stem cells (MSCs) influence T cells in health, disease and therapy through messengers of intercellular communication including extracellular vesicles (EVs). Apoptosis is a mode of cell death that tends to promote immune tolerance, and a large number of apoptotic vesicles (apoVs) are generated from MSCs during apoptosis. In an effort to characterize these apoVs and explore their immunomodulatory potential, here we show that after replenishing them systemically, the apoV deficiency in Fas mutant mice and pathological lymphoproliferation were rescued, leading to the amelioration of inflammation and lupus activity. ApoVs directly interacted with CD4⁺ T cells and inhibited CD25 expression and IL-2 production in a dose-dependent manner. A broad range of Th1/2/17 subsets and cytokines including IFNγ, IL17A and IL-10 were suppressed while Foxp3⁺ cells were maintained. Mechanistically, exposed phosphatidylserine (PtdSer/PS) on apoVs mediated the interaction with T cells to disrupt proximal T cell receptor signaling transduction. Remarkably, administration of apoVs prevented Th17 differentiation and memory formation, and ameliorated inflammation and joint erosion in murine arthritis. Collectively, our findings unveil a previously unrecognized crosstalk between MSC apoVs and CD4⁺ T cells and suggest a promising therapeutic use of apoVs for autoimmune diseases.
The importance of viral and cellular factors on flavivirus entry
2021, Current Opinion in Virology
The flavivirus are emerging and re-emerging arthropod-borne pathogens responsible for significant mortality and morbidity worldwide. The genus comprises more than 70 viruses, and despite genomic and structural similarities, infections by different flaviviruses result in different clinical presentations. In the absence of a safe and effective vaccine against these infections, the search for new strategies to inhibit viral infection is necessary.
The life cycle of arboviruses begins with the entry process composed of multiple steps: attachment, internalization, endosomal escape and capsid uncoating. This mini-review describes factors and mechanisms involved in the viral entry as events required to take over the cellular machinery and host factors and cellular pathways commonly used by flaviviruses as possible approaches for developing broad-spectrum antiviral drugs.
EPA and DHA can modulate cell death via inhibition of the Fas/tBid-mediated signaling pathway with ISKNV infection in grouper fin cell line (GF-1) cells
2020, Fish and Shellfish Immunology
Citation Excerpt :
The process of apoptotic cell death is controlled by a range of cell signaling pathways that originate either from the cell's external environment (extrinsic; receptor-mediated such as Fas) or from within the cell itself (intrinsic; mitochondria-mediated such as cytochrome c release) [20]. Apoptosis may be used by the host to limit the production of viruses or to disseminate them [21,22]. However, viruses themselves exploit the apoptosis process to produce sufficient virus progeny or to facilitate virus release [21–23].
Polyunsaturated fatty acids (PUFAs) play important roles in organisms, including the structure and liquidity of cell membranes, anti-oxidation and anti-inflammation. Very little has been done in terms of the effect of PUFAs on cell death, especially on DNA virus. In this study, we demonstrated that the infectious spleen and kidney necrosis virus (ISKNV) can induce host cell death via the apoptotic cell death pathway, which correlated to modulation by PUFAs in grouper fin cell line (GF-1) cells. We screened the PUFAs, including docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), for the ability of different dosages to prevent cell death in GF-1 cells with ISKNV infection. In the results, each 10 μM of DHA and EPA treatment enhanced host cell viability up to 80% at day 5 post-infection. Then, in Terminal deoxynucleotidyl transferase (TdT) dUTP Nick-End Labeling (TUNEL) assay, DHA- and EPA-treated groups reduced TUNEL positive signals 50% in GF-1 cells with ISKNV infection. Then, through studies of the mechanism of cell death, we found that ISKNV can induce both the Bax/caspase-3 and Fas/caspase-8/tBid death signaling pathways in GF-1 cells, especially at day 5 post-infection. Furthermore, we found that DHA and EPA treatment can either prevent caspase-3 activation on 17-kDa form cleavage or Bid cleaved (15-kDa form) for activation by caspase-8, apparently. On the other hand, the anti-apoptotic gene Bcl-2 was upregulated 0.3-fold and 0.15-fold at day 3 and day 5, respectively, compared to ISKNV-infected and DHA-treated cells; that this did not happen in the EPA-treated group showed that different PUFAs trigger different signals. Finally, ISKNV-infected GF-1 cells treated with either DHA or EPA showed a 5-fold difference in viral titer at day 5. Taken together, these results suggest that optimal PUFA treatment can affect cell death signaling through both the intrinsic and extrinsic death pathways, reducing viral expression and viral titer in GF-1 cells. This finding may provide insight in DNA virus infection and control.
Virus–Receptor Interactions: The Key to Cellular Invasion
2018, Journal of Molecular Biology
Virus–receptor interactions play a key regulatory role in viral host range, tissue tropism, and viral pathogenesis. Viruses utilize elegant strategies to attach to one or multiple receptors, overcome the plasma membrane barrier, enter, and access the necessary host cell machinery. The viral attachment protein can be viewed as the “key” that unlocks host cells by interacting with the “lock”—the receptor—on the cell surface, and these lock-and-key interactions are critical for viruses to successfully invade host cells. Many common themes have emerged in virus–receptor utilization within and across virus families demonstrating that viruses often target particular classes of molecules in order to mediate these events. Common viral receptors include sialylated glycans, cell adhesion molecules such as immunoglobulin superfamily members and integrins, and phosphatidylserine receptors. The redundancy in receptor usage suggests that viruses target particular receptors or “common locks” to take advantage of their cellular function and also suggests evolutionary conservation. Due to the importance of initial virus interactions with host cells in viral pathogenesis and the redundancy in viral receptor usage, exploitation of these strategies would be an attractive target for new antiviral therapeutics.
TIM-1 Ubiquitination Mediates Dengue Virus Entry
2018, Cell Reports
Dengue virus (DENV) is a major human pathogen causing millions of infections yearly. Despite intensive investigations, a DENV receptor that directly participates in virus internalization has not yet been characterized. Here, we report that the phosphatidylserine receptor TIM-1 is an authentic DENV entry receptor that plays an active role in virus endocytosis. Genetic ablation of TIM-1 strongly impaired DENV infection. Total internal reflection fluorescence microscopy analyses of live infected cells show that TIM-1 is mostly confined in clathrin-coated pits and is co-internalized with DENV during viral entry. TIM-1 is ubiquitinated at two lysine residues of its cytoplasmic domain, and this modification is required for DENV endocytosis. Furthermore, STAM-1, a component of the ESCRT-0 complex involved in intracellular trafficking of ubiquitinated cargos, interacts with TIM-1 and is required for DENV infection. Overall, our results show that TIM-1 is the first bona fide receptor identified for DENV.
Chimeric rabbit/human Fab antibodies against the hepatitis B e-antigen and their potential applications in assays, characterization, and therapy
2017, Journal of Biological Chemistry
Citation Excerpt :
In areas with a large population of HBV carriers, more than 90% of perinatal transmissions result in chronic hepatitis B (CHB). The factors that appear to establish CHB are the HBV e-antigen (HBeAg) and subviral particles composed of HBsAg (2, 3). The relationship between these antigens and the progression of CHB is complex (4).
Hepatitis B virus (HBV) infection afflicts millions worldwide, causing cirrhosis and liver cancer. HBV e-antigen (HBeAg), a clinical marker for disease severity, is a soluble variant of the viral capsid protein. HBeAg is not required for viral replication but is implicated in establishing immune tolerance and chronic infection. The structure of recombinant e-antigen (rHBeAg) was recently determined, yet to date, the exact nature and quantitation of HBeAg still remain uncertain. Here, to further characterize HBeAg, we used phage display to produce a panel of chimeric rabbit/human monoclonal antibody fragments (both Fab and scFv) against rHBeAg. Several of the Fab/scFv, expressed in Escherichia coli, had unprecedentedly high binding affinities (K_d ∼10⁻¹² m) and high specificity. We used Fab/scFv in the context of an enzyme-linked immunosorbent assay (ELISA) for HBeAg quantification, which we compared with commercially available kits and verified with seroconversion panels, the WHO HBeAg standard, rHBeAg, and patient plasma samples. We found that the specificity and sensitivity are superior to those of existing commercial assays. To identify potential fine differences between rHBeAg and HBeAg, we used these Fabs in microscale immunoaffinity chromatography to purify HBeAg from individual patient plasmas. Western blotting and MS results indicated that rHBeAg and HBeAg are essentially structurally identical, although HBeAg from different patients exhibits minor carboxyl-terminal heterogeneity. We discuss several potential applications for the humanized Fab/scFv.

View all citing articles on Scopus

View full text

Trends in Immunology

Viral apoptotic mimicry: an immune evasion strategy developed by the hepatitis B virus?

Abstract

Section snippets

HBsAg has anti-inflammatory potential similar to APCEs

HBsAg interacts with molecules that bind APCEs

Are circulating complement–HBsAg complexes preventing adaptive immunity towards the viral envelope proteins?

Concluding remarks

Biochem. Biophys. Res. Commun.

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

Hepatology

Curr. Opin. Immunol.

Blood

More than one way to die: apoptosis, necrosis and reactive oxygen damage

Oncogene

Viral subversion of the immune system

Annu. Rev. Immunol.

Viral mechanisms of immune evasion

Trends Microbiol.

Immune response to the hepatitis B virus: infection, animal models, vaccination

Viral Hepatitis. Rev.

Altered helper T-lymphocyte function associated with chronic hepatitis B virus infection and its role in response to therapeutic vaccination in humans

J. Immunol.

Dendritic cells and chronic hepatitis virus carriers

Intervirology

Immunosuppressive function of hepatitis B antigens in vitro: role of endoribonuclease V as one potential trans inactivator for cytokines in macrophages and human hepatoma cells

J. Virol.

Hepatitis B surface antigen suppresses the activation of monocytes through interaction with a serum protein and a monocyte-specific receptor

J. Gen. Virol.

Macrophages that have ingested apoptotic cells in vitro inhibit proinflammatory cytokine production through autocrine/paracrine mechanisms involving TGF-β, PGE2 and PAF

J. Clin. Invest.

Transcriptional and translational regulation of inflammatory mediator production by endogenous TGF-β in macrophages that have ingested apoptotic cells

J. Immunol.

Immunosuppressive effects of apoptotic cells

Nature

Lipopolysaccharide induces rapid production of IL-10 by monocytes in the presence of apoptotic neutrophils

J. Immunol.

Macrophages that have ingested apoptotic cells in vitro inhibit proinflammatory cytokine production through autocrine/paracrine mechanisms involving TGF-β, PGE₂ and PAF