scholarly journals THE MECHANISMS OF IMMUNE ESCAPE BY HEPATITIS B VIRUS

2017 ◽  
Vol 72 (6) ◽  
pp. 408-419 ◽  
Author(s):  
M. V. Sokolova ◽  
M. V. Konopleva ◽  
Т. A. Semenenko ◽  
V. G. Akimkin ◽  
A. V. Tutelyan ◽  
...  
Keyword(s):  
Immune Response ◽  
Immune System ◽  
Hepatitis B Virus ◽  
Hepatitis B ◽  
Immune Escape ◽  
Adaptive Immune Response ◽  
Host Cells ◽  
Cell Functions ◽  
Adaptive Immune ◽  
B Virus

The high prevalence of the hepatitis B virus (HBV) in population occurs mainly due to numerous mechanisms formed in the process of the virus evolution, contributing to its survival under immunological pressure. The review presents the most complete systematization and classification of various HBV protective mechanisms basing on their influence on different parts of congenital and adaptive immune response. The analysis of literature data allows for the conclusion that two basic principles underlie the mechanisms: the strategy of the «stealth virus» (virus’s escape from recognition by the immune system) and strategy of immunosuppression. The stealth virus strategy is performed as follows: special strategy of the HBV replication which prevents the recognition by the receptors of congenital immune system; occurrence of the vaccine escape mutants; isolation of the virus in host cells and tissues providing its inaccessibility to T-cells along with hyperproduction of subviral particles as traps for specific antibodies. The core principle of the immunosuppression implemented in hepatitis B therapy is based on the phenomenon of the viral apoptotic mimicry. The result of this interaction strategy is dysfunction of NK and NKT-cells, inactivation of dendritic cell functions, and suppression of the adaptive immune response. The review demonstrates that interaction between HBV and the immune system of the macro organism is in some kind of «dynamic equilibrium» depending on numerous factors. Specific molecular targets of the viral impact are described. We propose to expand the research on the influence of the host’s genetic factors on the development of congenital and adaptive immune response against HBV, especially during the real infectious process which results in the improvement of approaches to the therapy by developing personalized treatment methods.

scholarly journals Bacterial toxins and the immune system

2005 ◽  
Vol 201 (3) ◽  
pp. 321-323 ◽  
Author(s):  
Jorge E. Galán
Keyword(s):  
Immune Response ◽  
Immune System ◽  
Persistent Infection ◽  
Immune Cell ◽  
Adaptive Immune Response ◽  
Adaptive Immune System ◽  
Bacterial Toxins ◽  
Cell Functions ◽  
Adaptive Immune

Microorganisms that cause persistent infection often exhibit specific adaptations that allow them to avoid the adaptive immune response. Recently, several bacterial toxins have been shown in vitro to disrupt immune cell functions. However, it remains to be established whether these activities are relevant during infection and whether these toxins have specifically evolved to disrupt the adaptive immune system.

scholarly journals Understanding hepatitis B virus dynamics and the antiviral effect of interferon-α treatment in humanized chimeric mice

2020 ◽  
Author(s):  
Laetitia Canini ◽  
Yuji Ishida ◽  
Masataka Tsuge ◽  
Karina Durso-Cain ◽  
Tje Lin Chung ◽  
...  
Keyword(s):  
Hepatitis B Virus ◽  
Hepatitis B ◽  
Dna Synthesis ◽  
Mode Of Action ◽  
Adaptive Immune Response ◽  
Hbv Dna ◽  
Hbv Infection ◽  
Interferon Α ◽  
Adaptive Immune ◽  
B Virus

AbstractBackgroundWhereas the mode of action of lamivudine (LAM) against hepatitis B virus (HBV) is well established, the inhibition mechanism(s) of interferon-α are less completely defined. To advance our understanding, we mathematically modelled HBV kinetics during pegylated interferon-α-2a (pegIFN), LAM and pegIFN+LAM treatment of chronically HBV-infected humanized uPA/SCID chimeric mice.MethodsThirty-nine uPA/SCID mice with humanized livers whose pre-treatment steady-state serum HBV reached 9.2±0.4 logIU/mL were treated with pegIFN, LAM or pegIFN+LAM for 14 days. Serum HBV DNA and intracellular HBV DNA were measured frequently. We developed a nonlinear mixed effect viral kinetic model and simultaneously fit it to the serum and intracellular HBV DNA data.ResultsUnexpectedly, even in the absence of an adaptive-immune response, a biphasic decline in serum HBV DNA and intracellular HBV DNA was observed in response to all treatments. Modeling predicts that the first phase represents pegIFN inhibiting intracellular HBV DNA synthesis with efficacy of 86%, which was similar under LAM and pegIFN+LAM. In contrast, there were distinct differences in HBV decline during the 2nd phase which was accounted for in the model by a time-dependent inhibition of intracellular HBV DNA synthesis with the steepest decline observed during pegIFN+LAM (0.46/d) and the slowest (0.052/d) during pegIFN mono-treatment.ConclusionsReminiscent of observations in patients treated with pegIFN and/or LAM, a biphasic HBV decline was observed in treated humanized mice in the absence of adaptive immune response. Interestingly, combination treatment does not increase the initial inhibition of HBV production; however, enhancement of second phase decline is observed providing insight into the dynamics of HBV treatment response and the mode of action of interferon-α against HBV.Author SummaryChronic hepatitis B virus (HBV) infection remains a global health care problem as we lack sufficient curative treatment options. Elucidating the dynamic of HBV infection and treatment at the molecular level would potentially facilitate the development of novel, more effective HBV antivirals. Currently, the only well-established small animal HBV infection model available is the chimeric uPA/SCID mice with humanized livers; however, the HBV infection kinetics under interferon-α (IFN) in this model system have not been determined in sufficient detail to support the in-depth studies of HBV treatment response needed to identify/confirm more effective drug targets. In this study 39 chronic HBV-infected uPA/SCID humanized mice treated with IFN and/or lamivudine were analysed using a mathematical modelling approach. We found that IFN main mode of action is blocking HBV DNA synthesis and that 73% of synthesized HBV DNA per are secreted from infected cells. Our data-driven mathematical modeling study provides novel insights into IFN anti-HBV mechanism(s) and viral-host interplay at the molecular level.

scholarly journals Hepatitis B virus genomic nucleic acid in the activation and maturation of bone marrow-derived dendritic cells

2021 ◽  
pp. 109-119
Author(s):  
Chean Ring Leong ◽  
Tsukasa Seya ◽  
Woei Yenn Tong ◽  
Wen-Nee Tan
Keyword(s):  
Bone Marrow ◽  
Immune Response ◽  
Hepatitis B Virus ◽  
Nucleic Acid ◽  
Hepatitis B ◽  
Genomic Dna ◽  
Innate Immune ◽  
Adaptive Immune ◽  
B Virus

Hepatitis B virus (HBV) is the etiological agent that causes a self-limiting or chronic infection in the hepatocytes of about 250 million people worldwide. The role of adaptive immune system during HBV infection has been well studied. However, the innate immune system's responses against HBV during the early stage of infection largely remain unclear. In this study, we found that HBV genomic DNA or Salmon Sperm DNA (SSD) was able to induce the innate immune response in the macrophages cell line RAW264.7 but not the hepatocyte cell line, HepG2, indicating that hepatocytes may lack of a functional DNA-sensing pathway and hence are unable to respond to the presence of foreign DNA in the cytosol with type 1 IFN response. Thus, we hypothesized that non-parenchymal cells like the Antigen Presenting Cells (APC) might be crucial in triggering the initial immune response to suppress the virus replication and link the innate and adaptive responses. Using bone marrow-derived DCs (BMDC) as a model, this study demonstrated that HBV genomic DNA is able to induce cytokines like TNF-alpha, IL-6, and IL-12p40 secretion. We also examined the activation and maturation of BMDCs when exposed to the HBV genomic DNA intracellularly and extracellularly. A significant shift of CD86+ and CD40+ cell populations was observed during extracellular exposure of BMDC to Poly I:C and HBV genomic DNA, indicating that TLRs may be vital in the uptake of the extracellular viral DNA to activate the BMDCs. Moreover, transfection of intracellular nucleic acid stimuli, including HBV genomic DNA as well induced BMDCs maturation. Our findings highlight the critical function of DCs in antiviral response as a potential connection between the innate and adaptive immune systems during HBV pathogenesis. Nevertheless, further study is required to determine the role of cytosol DNA sensing pathway in DCs during HBV infection.

How Far we are towards Eradication of HBV Infection

2015 ◽  
Vol 24 (4) ◽  
pp. 473-479 ◽  
Author(s):  
Mihai Voiculescu
Keyword(s):  
Immune Response ◽  
Hepatitis B Virus ◽  
T Cell ◽  
Hepatitis B ◽  
T Cell Receptors ◽  
Hepatitis B Surface Antigen ◽  
Hbv Infection ◽  
Major Health Problem ◽  
Cell Receptors ◽  
B Virus

Hepatitis B virus (HBV) infection is a major health problem with an important biological and a significant socio-economic impact all over the world. There is a high pressure to come up with a new and more efficient strategy against HBV infection, especially after the recent success of HCV treatment. Preventing HBV infection through vaccine is currently the most efficient way to decrease HBV-related cirrhosis and liver cancer incidence, as well as the best way to suppress the HBV reservoir. The vaccine is safe and efficient in 80-95% of cases. One of its most important roles is to reduce materno-fetal transmission, by giving the first dose of vaccine in the first 24 hours after birth. Transmission of HBV infection early in life is still frequent, especially in countries with high endemicity.Successful HBV clearance by the host is immune-mediated, with a complex combined innate and adaptive cellular and humoral immune response. Different factors, such as the quantity and the sequence of HBV epitope during processing by dendritic cells and presenting by different HLA molecules or the polymorphism of T cell receptors (TOL) are part of a complex network which influences the final response. A new potential therapeutic strategy is to restore T-cell antiviral function and to improve innate and adaptive immune response by immunotherapeutic manipulation.It appears that HBV eradication is far from being completed in the next decades, and a new strategy against HBV infection must be considered. Abbreviations: ALT: alanine aminotransferase; APC: antigen presenting cells; cccDNA: covalently closed circular DNA; HBIG: hepatitis B immunoglobulin; HbsAg: hepatitis B surface antigen; HBV: hepatitis B virus; HCC: hepatocellular carcinoma; CTL: cytotoxic T lymphocyte; IFN: interferon; NUC: nucleos(t)ide analogues; pg RNA: pre genomic RNA; TLR: toll-like receptors; TOL: T cell receptors.

scholarly journals Immune Response to Hepatitis B Virus in Children with Papular Acrodermatitis

1977 ◽  
Vol 73 (5) ◽  
pp. 1103-1106 ◽  
Author(s):  
M. Colombo ◽  
M.A. Gerber ◽  
S.J. Vernace ◽  
F. Gianotti ◽  
F. Paronetto
Keyword(s):  
Immune Response ◽  
Hepatitis B Virus ◽  
Hepatitis B ◽  
B Virus

N-glycosylation mutations within hepatitis B virus surface major hydrophilic region contribute mostly to immune escape

2014 ◽  
Vol 60 (3) ◽  
pp. 515-522 ◽  
Author(s):  
De-Min Yu ◽  
Xin-Hua Li ◽  
Vannary Mom ◽  
Zhong-Hua Lu ◽  
Xiang-Wei Liao ◽  
...  
Keyword(s):  
Hepatitis B Virus ◽  
Hepatitis B ◽  
Immune Escape ◽  
Major Hydrophilic Region ◽  
Virus Surface ◽  
B Virus ◽  
Hydrophilic Region

Cellular immune response to hepatitis B virus antigens

1988 ◽  
Vol 7 (1) ◽  
pp. 21-33 ◽  
Author(s):  
C. Ferrari ◽  
A. Penna ◽  
A. DegliAntoni ◽  
F. Fiaccadori
Keyword(s):  
Immune Response ◽  
Hepatitis B Virus ◽  
Hepatitis B ◽  
Cellular Immune Response ◽  
B Virus ◽  
Hepatitis B Virus Antigens ◽  
Virus Antigens ◽  
Cellular Immune

NTCP oligomerization occurs downstream of the NTCP-EGFR interaction during hepatitis B virus internalization

2021 ◽  
Author(s):  
Kento Fukano ◽  
Mizuki Oshima ◽  
Senko Tsukuda ◽  
Hideki Aizaki ◽  
Mio Ohki ◽  
...  
Keyword(s):  
Epidermal Growth Factor Receptor ◽  
Bile Acid ◽  
Hepatitis B Virus ◽  
Hepatitis B ◽  
Viral Entry ◽  
Sodium Taurocholate ◽  
Growth Factor Receptor ◽  
Host Cells ◽  
B Virus ◽  
Epidermal Growth

Sodium taurocholate cotransporting polypeptide (NTCP) is a receptor that is essential for hepatitis B virus (HBV) entry into the host cell. A number of HBV entry inhibitors targeting NTCP have been reported to date; these inhibitors have facilitated a mechanistic analysis of the viral entry process. However, the mechanism of HBV internalization into host cells after interaction of virus with NTCP remains largely unknown. Recently, we reported that troglitazone, a thiazolidinedione derivative, specifically inhibits both HBV internalization and NTCP oligomerization, resulting in inhibition of HBV infection. Here, using troglitazone as a chemical probe to investigate entry process, the contribution of NTCP oligomerization to HBV internalization was evaluated. Using surface plasmon resonance and transporter kinetics, we found that troglitazone directly interacts with NTCP and non-competitively interferes with NTCP-mediated bile acid uptake, suggesting that troglitazone allosterically binds to NTCP, rather than to the bile acid-binding pocket. Additionally, alanine scanning mutagenesis showed that a mutation at phenylalanine 274 of NTCP (F274A) caused a loss of HBV susceptibility and disrupted both the oligomerization of NTCP and HBV internalization without affecting viral attachment to the cell surface. An inhibitor of the interaction between NTCP and epidermal growth factor receptor (EGFR), another host cofactor essential for HBV internalization, impeded NTCP oligomerization. Meanwhile, co-immunoprecipitation analysis revealed that neither troglitazone nor the F274A mutation in NTCP affect the NTCP-EGFR interaction. These findings suggest that NTCP oligomerization is initiated downstream of the NTCP-EGFR interaction, and then triggers HBV internalization. This study provides significant insight into the HBV entry mechanisms. Importance Hepatitis B virus (HBV) infection is mediated by a specific interaction with sodium taurocholate cotransporting polypeptide (NTCP), a viral entry receptor. Although the virus-receptor interactions are believed to trigger viral internalization into host cells, the exact molecular mechanisms of HBV internalization are not understood. In this study, we revealed the mode of action whereby troglitazone, a specific inhibitor of HBV internalization, impedes NTCP oligomerization, and identified NTCP phenylalanine 274 as a residue essential for this oligomerization. We further analyzed the association between NTCP oligomerization and HBV internalization, a process that is mediated by epidermal growth factor receptor (EGFR), another essential host cofactor for HBV internalization. Our study provides critical information on the mechanism of HBV entry, and suggests that oligomerization of the viral receptor serves as an attractive target for drug discovery.

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