Editor's Note: Hepatitis B virus (HBV), a hepatotropic DNA virus, is the causative agent of hepatitis B. HBV-infected individuals have three types of particles in their blood: Dane particles, spherical particles, and tubular particles. The characteristics of these particles can be used to detect evidence of HBV infection through immunological methods. Recently, at the 17th National Conference on Clinical Hepatology, Professor Ailong Huang, President of Chongqing Medical University, delivered a report titled "Mechanisms of Persistent HBV Infection." This report provides an in-depth analysis of the mechanisms behind persistent HBV infection, revealing the relationship between abnormal host immune responses and viral evasion of host antiviral effects, offering new perspectives for understanding HBV persistence and developing treatment strategies.Virus-Host Interactions and Persistent HBV Infection
As a parasitic pathogen, HBV encodes only a portion of the factors necessary for its complete life cycle, relying on host cells to provide various molecular machines, such as transcription and translation machinery, to produce progeny viruses and maintain its population. From an evolutionary perspective, any existing virus is the result of natural selection, demonstrating better adaptation to the environment compared to its extinct counterparts, if any.
For viruses, the most crucial environment is the host. Outside the host environment, viruses do not survive long and cannot produce progeny. However, viruses are generally harmful to the host, unlike the beneficial mutualistic relationship seen with the normal gut microbiota. The host’s response to viral infection is typically to reject and eliminate the virus through innate and specific immune responses. Viruses adapt to these defenses through evolutionary changes. Some viruses, like influenza and SARS-CoV-2, are cleared in a short period (acute infection) but have high transmissibility and can infect new hosts before being eliminated. Other viruses adopt a chronic infection strategy, accumulating significant opportunities to infect new hosts over prolonged periods, ensuring population continuation. Viruses causing chronic infections include DNA viruses like EBV, HBV, HPV, HSV-1, and RNA viruses like HCV, HDV, HIV, and measles virus, infecting various organs and tissues such as the liver, kidneys, immune cells, endothelial cells, neurons, and lungs.
Immune Evasion and Chronic Infection
Chronic viral infection is likely a result of the co-evolutionary battle between the virus and host. Successful persistent infection requires evasion of the host’s innate and specific immune responses. For HBV, the host’s specific immune response is crucial in limiting the transition from acute to chronic HBV infection. This has been supported by experiments in chimpanzees, where continuous depletion of CD4+ T cells before and after virus inoculation resulted in undetectable CD8+ T cell responses and chronic infection (>70 weeks, compared to self-clearance in <28 weeks in controls). Removing CD8+ T cells during the peak of HBV DNA levels in week six post-infection led to sustained high viral levels, with virus clearance only starting after CD8+ T cell numbers began to recover. Thus, specific immune tolerance is a reasonable explanation for most chronic HBV infections.
The mechanisms of specific immune tolerance are not fully understood, hindering the development of strategies to reverse this state. The typical specific immune response includes four processes: antigen presentation, specific CD4+ T cell activation, CD8+ T cell activation, and B cell activation. Abnormalities in any or all of these processes are likely involved in chronic HBV infection. Previous reviews have suggested issues with the activation of specific CD4+ and CD8+ T cells. Persistent viral antigens are considered a key factor in inducing immune tolerance.
Central Tolerance and Peripheral Immune Modulation
Recent findings from Professor Zhenghong Yuan’s lab showed that monocytic myeloid-derived suppressor cells (mMDSCs) carrying HBs T cell epitopes can enter the thymus and present them to developing CD8+ T cells, leading to clonal deletion. This supports the idea of central tolerance in chronic HBV infection. Professor Ning-Shao Xia’s team also discovered that high levels of persistent HBsAg could cause defects in the differentiation of plasma cells induced by therapeutic vaccines. Suppressing HBsAg with therapeutic antibodies before vaccination significantly improved plasma cell generation and functional antibody production, enhancing HBsAg clearance.
The impact of clonal deletion depends on the dynamics of naive T cells. If the diversity of the T cell repertoire is determined primarily in early life, perinatal clonal deletion could have long-term effects, making it challenging to restore specific immunity even after removing persistent high antigen loads. Conversely, if thymic diversity continues to update significantly in adulthood, removing persistent suppressive factors might restore HBV-specific immunity. Studies indicate that the thymus’s ability to produce new T cells declines sharply after puberty, ceasing around age 40, after which the peripheral naive T cell pool relies on the proliferation of existing cells. Thus, restoring HBV-specific immunity in chronic hepatitis B patients would depend on reactivating existing T cell clones. The critical question is whether fully activating these “exhausted” T cell clones is possible, and if so, how. The answers to these questions will determine the strategies for rebuilding HBV-specific immunity in chronic hepatitis B patients.
Viral Evasion of Innate Immunity
In addition to specific immune responses, viral evasion of innate immune surveillance may also contribute to persistent infection. Early research indicated that HBV infection in chimpanzees did not elicit a significant innate immune response, unlike HCV infection, leading to the concept of HBV as a stealth virus. From a co-evolutionary perspective, viruses that do not trigger host defense responses have a survival advantage, as do those that actively suppress host defenses.
Host cell antiviral strategies include inducible or reactive expression of antiviral factors (e.g., ISGs or other antiviral proteins in response to IFN-α or TNF-α) and constitutive expression of antiviral factors. While inducible mechanisms are well-studied, constitutive mechanisms have received less attention. Recent explorations in this area revealed that FUBP1, identified through systematic screening using a STAT1 promoter activity reporter cell model and shRNA library, is a novel STAT1 negative regulator. HBV pgRNA significantly upregulates FUBP1 expression, which, in turn, inhibits STAT1 expression and downregulates constitutive ISG expression by affecting histone modifications in the STAT1 promoter region. Additionally, HNRNPU, a positive regulator of ISG expression, can inhibit HBV transcription through the OAS-RNase L system, while HBx-DDB1 interactions downregulate HNRNPU expression to counteract innate immunity.
Conclusion
The mechanisms of persistent HBV infection involve both abnormal host-specific immune responses and viral evasion or suppression of host antiviral effects. For innate immunity, HBV avoids activating antiviral responses through stealth strategies and actively inhibits constitutive ISG expression. For specific immunity, early persistent high antigen loads may induce immune tolerance. Research on the relationship between chronic HBV infection and specific immune abnormalities faces challenges due to the lack of good small animal infection models, making it difficult to establish causality. This also hampers the development of immune strategies for restoring specific immune responses. However, recent clinical trial results with antisense oligonucleotide (ASO) drugs, which effectively reduce HBsAg levels and potentially modulate immunity, offer new opportunities for understanding and addressing persistent HBV infection.
