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Annual Review of Immunology Jun 2024The liver's unique characteristics have a profound impact on the priming and maintenance of adaptive immunity. This review delves into the cellular circuits that... (Review)
Review
The liver's unique characteristics have a profound impact on the priming and maintenance of adaptive immunity. This review delves into the cellular circuits that regulate adaptive immune responses in the liver, with a specific focus on hepatitis B virus infection as an illustrative example. A key aspect highlighted is the liver's specialized role in priming CD8+ T cells, leading to a distinct state of immune hyporesponsiveness. Additionally, the influence of the liver's hemodynamics and anatomical features, particularly during liver fibrosis and cirrhosis, on the differentiation and function of adaptive immune cells is discussed. While the primary emphasis is on CD8+ T cells, recent findings regarding the involvement of B cells and CD4+ T cells in hepatic immunity are also reviewed. Furthermore, we address the challenges ahead and propose integrating cutting-edge techniques, such as spatial biology, and combining mouse models with human sample analyses to gain comprehensive insights into the liver's adaptive immunity. This understanding could pave the way for novel therapeutic strategies targeting infectious diseases, malignancies, and inflammatory liver conditions like metabolic dysfunction-associated steatohepatitis and autoimmune hepatitis.
Topics: Humans; Animals; Adaptive Immunity; Liver; CD8-Positive T-Lymphocytes; Hepatitis B virus; Hepatitis B; B-Lymphocytes; CD4-Positive T-Lymphocytes
PubMed: 38360545
DOI: 10.1146/annurev-immunol-090122-041354 -
Antiviral Therapy Aug 2023In endemic areas, hepatitis C virus (HCV)/hepatitis B virus (HBV) coinfection is common, and patients with coinfection have a higher risk of developing liver disease... (Review)
Review
In endemic areas, hepatitis C virus (HCV)/hepatitis B virus (HBV) coinfection is common, and patients with coinfection have a higher risk of developing liver disease such as hepatocellular carcinoma, liver fibrosis and cirrhosis. In such cases, HCV predominates, and HBV replication is suppressed by HCV. HCV core proteins and interferons that are activated by HCV are responsible for the suppression of HBV. Immunosuppression is also seen in patients with HCV and HBV coinfections. A decrease in HCV-neutralizing antibody response and circulation of Th1-like Tfh cells is observed in patients with HCV and HBV coinfection. Both viruses interacted in the liver, and treatment of HCV/HBV coinfection is genotype-based and complex due to the interaction of both viruses. In HCV-dominant cases, direct-acting antiviral drugs and peg interferon plus ribavirin are used for the treatment, with continuous monitoring of AST and ALT. HBV-dominant cases are less common and are treated with peg interferon and nucleoside nucleotide analogues with monitoring of AST and ALT. The SVR rate in HCV-HBV coinfection is higher than that in monoinfection when treated with direct-acting antiviral drugs. But there is a risk of reactivation of HBV during and after therapy. The rate of reactivation is lower in patients treated with direct-acting antiviral drugs as compared to those treated with peg interferon plus ribavirin. Biomarkers of HBV such as HBcrAg, HBV DNA and HBVpg RNA are not effective in the prediction of HBV reactivation; only the hepatitis B surface antigen titre can be used as a biomarker for HBV reactivation. HCV can also be reactive, but this is found in very rare cases in which HBV is present and is treated first.
Topics: Humans; Hepatitis B virus; Antiviral Agents; Coinfection; Hepacivirus; Hepatitis C, Chronic; Ribavirin; Liver Cirrhosis; Interferons; Liver Neoplasms
PubMed: 37489502
DOI: 10.1177/13596535231189643 -
Clinical Medicine (London, England) Jul 2023Hepatitis D virus (HDV), also referred to as hepatitis delta virus, is the smallest virus capable of causing human disease. It is unable to replicate on its own and can... (Review)
Review
Hepatitis D virus (HDV), also referred to as hepatitis delta virus, is the smallest virus capable of causing human disease. It is unable to replicate on its own and can only propagate in the presence of hepatitis B virus (HBV). Infection with both HBV and HDV frequently results in more severe disease than HBV alone, with higher instances of cirrhosis, liver failure and hepatocellular carcinoma (HCC). Thus, there is a need for effective treatment for HDV; however, currently approved treatment options are very limited both in terms of their efficacy and availability. This makes the management of HDV a challenge for physicians. In this review, we look at the background, diagnosis and treatment of HDV, informed by our hospital data, to set out the optimal management of HDV; we also explore novel treatment options for this disease.
Topics: Humans; Hepatitis Delta Virus; Antiviral Agents; Carcinoma, Hepatocellular; Liver Neoplasms; Hepatitis B virus
PubMed: 37353306
DOI: 10.7861/clinmed.2022-0556 -
Journal of Medical Virology Sep 2023Hepatitis B virus (HBV) covalently closed circular DNA (cccDNA), the transcription template for all viral mRNAs, is highly stable and current treatment options...
Hepatitis B virus (HBV) covalently closed circular DNA (cccDNA), the transcription template for all viral mRNAs, is highly stable and current treatment options cannot effectively induce its clearance. Previously, we established an HBV persistence mouse model based on a clinical isolate (termed BPS) and identified interleukin-21 (IL-21) as a potent inducer of HBV clearance. Lipid nanoparticle (LNP) mediated delivery of mRNA has proven to be a highly safe and effective delivery platform. This work explored the applicability and effectiveness of the mRNA-LNP platform in IL-21-based HBV therapies. First, LNP-encapsulated murine IL-21 mRNA (LNP-IL-21) was prepared, characterized, and demonstrated to engender IL-21 expression in vitro and in vivo. Next, LNP-IL-21 was shown to induce clearance of both serum and intrahepatic HBV antigen and DNA in two HBV persistence mouse models based on BPS and recombinant cccDNA (rcccDNA), respectively, which was associated with HBV-specific humoral and cellular immune responses. Furthermore, peripheral blood mononuclear cells from BPS persistence mice treated ex vivo with LNP-IL-21 and HBV surface antigen (HBsAg) could induce similar HBV clearance upon infusion into recipient mice. These findings indicated that IL-21 combined with mRNA-LNP platform represents a valid and promising strategy for developing novel therapeutics against chronic HBV infection.
Topics: Animals; Mice; Hepatitis B virus; Leukocytes, Mononuclear; Hepatitis B Surface Antigens; Disease Models, Animal; RNA, Messenger
PubMed: 37665238
DOI: 10.1002/jmv.29062 -
Hepatology Communications Sep 2023HBV infection causes chronic liver disease and leads to the development of HCC. To identify host factors that support the HBV life cycle, we previously established the...
BACKGROUND
HBV infection causes chronic liver disease and leads to the development of HCC. To identify host factors that support the HBV life cycle, we previously established the HC1 cell line that maintains HBV infection and identified host genes required for HBV persistence.
METHODS
The present study focused on endothelial lipase (LIPG), which binds to heparan sulfate proteoglycans (HSPGs) in the cell membrane.
RESULTS
We found HBV infection was impaired in humanized liver chimeric mouse-derived hepatocytes that were transduced with lentivirus expressing short hairpin RNA against LIPG. Long-term suppression of LIPG combined with entecavir further suppressed HBV replication. LIPG was shown to be involved in HBV attachment to the cell surface by using 2 sodium taurocholate cotransporting peptide (NTCP)-expressing cell lines, and the direct interaction of LIPG and HBV large surface protein was revealed. Heparin and heparinase almost completely suppressed the LIPG-induced increase of HBV attachment, indicating that LIPG accelerated HBV attachment to HSPGs followed by HBV entry through NTCP. Surprisingly, the attachment of a fluorescently labeled NTCP-binding preS1 probe to NTCP-expressing cells was not impaired by heparin, suggesting the HSPG-independent attachment of the preS1 probe to NTCP. Interestingly, attachment of the preS1 probe was severely impaired in LIPG knockdown or knockout cells. Inhibitors of the lipase activity of LIPG similarly impaired the attachment of the preS1 probe to NTCP-expressing cells.
CONCLUSIONS
LIPG participates in HBV infection by upregulating HBV attachment to the cell membrane by means of 2 possible mechanisms: increasing HBV attachment to HSPGs or facilitating HSPG-dependent or HSPG-independent HBV attachment to NTCP by its lipase activity.
Topics: Animals; Mice; Heparan Sulfate Proteoglycans; Heparin; Hepatitis B; Hepatitis B virus; Lipase
PubMed: 37655967
DOI: 10.1097/HC9.0000000000000206 -
Nature Communications Dec 2023Autophagy receptor NDP52 triggers bacterial autophagy against infection. However, the ability of NDP52 to protect against viral infection has not been established. We...
Autophagy receptor NDP52 triggers bacterial autophagy against infection. However, the ability of NDP52 to protect against viral infection has not been established. We show that NDP52 binds to envelope proteins of hepatitis B virus (HBV) and triggers a degradation process that promotes HBV clearance. Inactivating NDP52 in hepatocytes results in decreased targeting of viral envelopes in the lysosome and increased levels of viral replication. NDP52 inhibits HBV at both viral entry and late replication stages. In contrast to NDP52-mediated bacterial autophagy, lysosomal degradation of HBV envelopes is independent of galectin 8 and ATG5. NDP52 forms complex with Rab9 and viral envelope proteins and links HBV to Rab9-dependent lysosomal degradation pathway. These findings reveal that NDP52 acts as a sensor for HBV infection, which mediates a unique antiviral response to eliminate the virus. This work also suggests direct roles for autophagy receptors in other lysosomal degradation pathways than canonical autophagy.
Topics: Humans; Hepatitis B virus; Hepatitis B; Hepatocytes; Autophagy; Lysosomes; Antiviral Agents; Virus Replication
PubMed: 38114531
DOI: 10.1038/s41467-023-44201-2 -
Journal of Immunology Research 2024Hepatitis B virus (HBV) infection is a major global health issue and ranks among the top causes of liver cirrhosis and hepatocellular carcinoma. Although current... (Review)
Review
Hepatitis B virus (HBV) infection is a major global health issue and ranks among the top causes of liver cirrhosis and hepatocellular carcinoma. Although current antiviral medications, including nucleot(s)ide analogs and interferons, could inhibit the replication of HBV and alleviate the disease, HBV cannot be fully eradicated. The development of cellular and animal models for HBV infection plays an important role in exploring effective anti-HBV medicine. During the past decades, advancements in several cell culture systems, such as HepG2.2.15, HepAD38, HepaRG, hepatocyte-like cells, and primary human hepatocytes, have propelled the research in inhibiting HBV replication and expression and thus enriched our comprehension of the viral life cycle and enhancing antiviral drug evaluation efficacy. Mouse models, in particular, have emerged as the most extensively studied HBV animal models. Additionally, the present landscape of HBV therapeutics research now encompasses a comprehensive assessment of the virus's life cycle, targeting numerous facets and employing a variety of immunomodulatory approaches, including entry inhibitors, strategies aimed at cccDNA, RNA interference technologies, toll-like receptor agonists, and, notably, traditional Chinese medicine (TCM). This review describes the attributes and limitations of existing HBV model systems and surveys novel advancements in HBV treatment modalities, which will offer deeper insights toward discovering potentially efficacious pharmaceutical interventions.
Topics: Humans; Animals; Hepatitis B virus; Antiviral Agents; Disease Models, Animal; Hepatitis B; Virus Replication; Mice; Hepatocytes
PubMed: 38745751
DOI: 10.1155/2024/4722047 -
Clinics in Liver Disease Nov 2023The natural history of hepatitis B virus (HBV) infection is closely dependent on the dynamic interplay between the host immune response and viral replication.... (Review)
Review
The natural history of hepatitis B virus (HBV) infection is closely dependent on the dynamic interplay between the host immune response and viral replication. Spontaneous HBV clearance in acute self-limited infection is the result of an adequate and efficient antiviral immune response. Instead, it is widely recognized that in chronic HBV infection, immunologic dysfunction contributes to viral persistence. Long-lasting exposure to high viral antigens, upregulation of multiple co-inhibitory receptors, dysfunctional intracellular signaling pathways and metabolic alterations, and intrahepatic regulatory mechanisms have been described as features ultimately leading to a hierarchical loss of effector functions up to full T-cell exhaustion.
Topics: Humans; Hepatitis B virus; Hepatitis B Surface Antigens; Hepatitis B, Chronic; Hepatitis B; Virus Replication
PubMed: 37778772
DOI: 10.1016/j.cld.2023.05.001 -
Viruses Dec 2023The hepatitis B virus (HBV) continues to cause substantial health and economic burdens, and its target of elimination may not be reached in 2030 without further efforts... (Review)
Review
The hepatitis B virus (HBV) continues to cause substantial health and economic burdens, and its target of elimination may not be reached in 2030 without further efforts in diagnostics, non-pharmaceutical prevention measures, vaccination, and treatment. Current therapeutic options in chronic HBV, based on interferons and/or nucleos(t)ide analogs, suppress the virus replication but do not eliminate the pathogen and suffer from several constraints. This paper reviews the progress on biotechnological approaches in functional and definitive HBV treatments, including gene-editing tools, i.e., zinc-finger proteins, transcription activator-like effector nucleases, and CRISPR/Cas9, as well as therapeutics based on RNA interference. The advantages and challenges of these approaches are also discussed. Although the safety and efficacy of gene-editing tools in HBV therapies are yet to be demonstrated, they show promise for the revitalization of a much-needed advance in the field and offer viral eradication. Particular hopes are related to CRISPR/Cas9; however, therapeutics employing this system are yet to enter the clinical testing phases. In contrast, a number of candidates based on RNA interference, intending to confer a functional cure, have already been introduced to human studies. However, larger and longer trials are required to assess their efficacy and safety. Considering that prevention is always superior to treatment, it is essential to pursue global efforts in HBV vaccination.
Topics: Humans; RNA Interference; CRISPR-Cas Systems; Genetic Therapy; DNA, Viral; Hepatitis B; Hepatitis B, Chronic; Hepatitis B virus; Antiviral Agents
PubMed: 38140636
DOI: 10.3390/v15122395 -
Experimental Cell Research Sep 2023The hepatitis B Virus X (HBx) protein plays a crucial role in the HBV-induced hepatic steatosis. Fatty acid transport protein 2 (FATP2) is a key protein that is involved...
The hepatitis B Virus X (HBx) protein plays a crucial role in the HBV-induced hepatic steatosis. Fatty acid transport protein 2 (FATP2) is a key protein that is involved in hepatic lipogenesis, and it was found to be highly expressed in various metabolic diseases. However, Whether FATP2 is a key factor in the pathogenesis of HBx-induced hepatic steatosis remains unclear. In this study, we found that FATP2 was up-regulated by HBx in vitro and in vivo and participated in HBx-induced hepatic lipid accumulation. Treatment of HBx-expressing cell lines and mice with FATP2 inhibitor (FATP2i) lipofermata ameliorated HBx-induced lipid accumulation and reduced oxidative stress and inflammation caused by lipid accumulation. Moreover, the liver injury of mouse was restored after FATP2i treatment. In summary, our results reveal that FATP2 is a key driver factor for HBx-induced hepatic lipid accumulation, and inhibition of FATP2 can ameliorates lipid accumulation caused by HBx. This study provides new insights into the mechanism of HBV-induced hepatic steatosis.
Topics: Mice; Animals; Up-Regulation; Fatty Liver; Cell Line; Lipids; Hepatitis B virus
PubMed: 37437769
DOI: 10.1016/j.yexcr.2023.113721