Research Progress in Host Immune Response During Hepatitis B Virus Infection
Hepatitis B virus (HBV) infection remains a critical global health challenge, responsible for severe liver pathologies such as cirrhosis and hepatocellular carcinoma. HBV’s non-cytopathic nature means hepatocyte damage arises primarily from immune-mediated inflammation and fibrosis. Despite advances in antiviral therapy, functional cure—defined as sustained loss of hepatitis B surface antigen (HBsAg) and undetectable HBV DNA—remains elusive for most chronic hepatitis B (CHB) patients. Insights from spontaneous resolution of acute and chronic infections highlight the pivotal role of the immune system in controlling HBV. This review synthesizes recent advances in understanding innate and adaptive immune responses during HBV infection, emphasizing mechanisms of viral persistence and emerging therapeutic strategies.
Innate Immune Responses to HBV Infection
The innate immune system serves as the first line of defense against viral infections. Pathogen recognition receptors (PRRs), such as Toll-like receptors (TLRs) and nucleotide-binding oligomerization domain (NOD)-like receptors, detect pathogen-associated molecular patterns (PAMPs) to initiate antiviral signaling. HBV was historically considered a “stealth virus” due to its minimal induction of innate immunity. However, recent studies challenge this notion, revealing nuanced interactions between HBV and innate immune components.
Intrahepatic gene expression profiling in CHB patients demonstrates significant downregulation of interferon (IFN)-stimulated genes (ISGs) and PRR signaling pathways compared to uninfected individuals. This suppression is not directly correlated with viral load, suggesting HBV employs mechanisms to evade innate detection. For example, HBV particles or antigens may interfere with PRR activation or downstream signaling, dampening the production of pro-inflammatory cytokines like type I IFNs. Despite this immune evasion, certain PRR agonists, such as NOD1 ligands, have shown promise in preclinical models. Stimulating the NOD1 pathway enhances the maturation of liver sinusoidal endothelial cells (LSECs) and dendritic cells (DCs), leading to robust T-cell activation and suppression of HBV replication.
LSECs, specialized antigen-presenting cells (APCs) in the liver, play dual roles in HBV infection. Under steady-state conditions, LSECs promote immune tolerance by inducing CD4+ and CD8+ T-cell anergy. However, activation signals—such as matrix metalloproteinase (MMP)-2/9-mediated cleavage of CD100—can convert LSECs into immunostimulatory APCs. Soluble CD100 (sCD100) interacts with its receptor CD72 on LSECs, enhancing their ability to prime HBV-specific CD8+ T cells and accelerate viral clearance. Similarly, Kupffer cells (KCs), liver-resident macrophages, exhibit a regulatory M2 phenotype in CHB, secreting anti-inflammatory cytokines like IL-10 while suppressing pro-inflammatory IL-6 and IL-1β. This skewed KC polarization contributes to a tolerogenic microenvironment that facilitates viral persistence.
Plasmacytoid dendritic cells (pDCs), major producers of type I IFNs, are another key innate immune player. In CHB, pDC functionality is paradoxically enhanced during the transition from the immune-tolerant (IT) phase to the hepatitis-active phase, with elevated IFN-α levels correlating with disease activity. These findings imply that pDC activation might drive immunopathology rather than viral control in chronic infection.
Adaptive Immune Responses: T Cells and B Cells in HBV Control
Adaptive immunity, particularly HBV-specific T and B cells, is central to resolving acute HBV infection. In CHB, however, these responses are often dysfunctional, permitting viral persistence.
HBV-Specific T-Cell Responses
CD8+ T cells are critical for eliminating HBV-infected hepatocytes. Chronic infection is characterized by T-cell exhaustion, marked by upregulated inhibitory receptors (e.g., PD-1, Tim-3) and impaired effector functions. Recent studies using peptide-MHC tetramers reveal that HBV core- and polymerase-specific CD8+ T cells in CHB patients with low viral loads retain a memory-like phenotype rather than terminal exhaustion. These cells exhibit heterogeneity in frequency, phenotype, and function depending on the targeted epitope and disease stage. For instance, core-specific CD8+ T cells demonstrate greater proliferative capacity and cytokine production than polymerase-specific counterparts.
IL-21, produced by CD4+ T follicular helper cells, plays a vital role in reinvigorating exhausted CD8+ T cells. IL-21 enhances proliferation, reduces PD-1 expression, and restores cytotoxic function in HBV-specific CD8+ T cells, underscoring its therapeutic potential. Additionally, discontinuation of nucleos(t)ide analog (NA) therapy triggers dynamic changes in T-cell responsiveness. Patients who achieve HBsAg loss post-NA cessation exhibit T cells with reduced exhaustion markers, and PD-1/PD-L1 blockade further amplifies HBV-specific CD4+ and CD8+ T-cell responses.
HBV-Specific B-Cell Responses
B cells have been understudied in HBV immunity, but recent advances highlight their role in both viral control and immune evasion. HBV core antigen (HBcAg)-specific B cells are more frequent and functionally mature than HBsAg-specific B cells in CHB patients. HBsAg-specific B cells display impaired antibody production, mirroring the absence of anti-HBs antibodies in chronic infection. These dysfunctional B cells exhibit an atypical memory phenotype with elevated PD-1 expression.
PD-1 blockade partially restores HBsAg-specific B-cell function, enhancing their differentiation into antibody-secreting plasmablasts. Furthermore, cytokine supplementation (e.g., IL-2 and IL-21) improves B-cell maturation in vitro, suggesting combinatory immunotherapies could overcome B-cell exhaustion.
The Intrahepatic Immune Microenvironment and Therapeutic Implications
The liver’s unique immune microenvironment, enriched with tolerogenic APCs and regulatory cytokines, fosters HBV persistence. LSECs, KCs, and hepatic stellate cells collaboratively suppress effector T-cell responses while promoting regulatory T-cell (Treg) expansion. Additionally, HBV antigens like HBeAg modulate immune cell function, further dampening antiviral immunity.
Targeting this immunosuppressive milieu is a focus of current research. Strategies include:
- PRR Agonists: Activating NOD1 or TLR pathways to enhance APC maturation and T-cell priming.
- Checkpoint Inhibition: Blocking PD-1/PD-L1 or Tim-3 to reinvigorate exhausted T cells.
- Cytokine Therapy: Administering IL-21 or IFN-α to boost T-cell and B-cell function.
- B-Cell Modulation: Combining PD-1 blockade with cytokines to restore antibody production.
Challenges and Future Directions
While immunotherapies hold promise, challenges remain. HBV’s high mutation rate and cccDNA persistence necessitate combinatory approaches targeting both viral replication and immune dysfunction. Additionally, the risk of immune-mediated liver injury during therapy requires careful monitoring. Future studies should delineate biomarkers predictive of treatment response and identify novel targets within the HBV life cycle or immune evasion pathways.
Conclusion
Advances in understanding HBV immunopathogenesis have illuminated the complex interplay between viral evasion strategies and host immunity. Restoring functional innate and adaptive immune responses, particularly through combinatory therapies, represents a viable path toward achieving functional cure. Continued research into intrahepatic immune dynamics and personalized immunomodulatory regimens will be critical for overcoming the challenges of chronic HBV infection.
doi.org/10.1097/CM9.0000000000001096
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