Abstract
Hepatitis B virus (HBV) infection is the major cause of inflammatory liver disease, of which the clinical recovery and effective anti-viral therapy is associated with the sustained viral control of effector T cells. In humans, chronic HBV infection often shows weak or absent virus-specific T-cell reactivity, which is described as the ‘exhaustion' state characterized by poor effector cytotoxic activity, impaired cytokine production and sustained expression of multiple inhibitory receptors, such as programmed cell death-1 (PD-1), lymphocyte activation gene-3, cytotoxic T lymphocyte-associated antigen-4 and CD244. As both CD4+ and CD8+ T cells participate in the immune responses against chronic hepatitis virus through distinct manners, compelling evidences have been proposed, which restore the anti-viral function of these exhausted T cells by blocking those inhibitory receptors with its ligand and will pave the way for the development of more effective immunotherapeutic and prophylactic strategies for the treatment of chronic infectious diseases. A large number of studies have stated the essentiality of T-cell exhaustion in virus-infected diseases, such as LCMV, hepatitis C virus (HCV), human immunodeficiency virus infections and cancers. Besides, the functional restoration of HCV- and HIV-specific CD8+ T cells by PD-1 blockade has already been repeatedly verified, and also for the immunological control of tumors in humans, blocking the PD-1 pathway could be a major immunotherapeutic strategy. Although the specific molecular pathways of T-cell exhaustion remain ambiguous, several transcriptional pathways have been implicated in T-cell exhaustion recently; among them Blimp-1, T-bet and NFAT2 were able to regulate exhausted T cells during chronic viral infection, suggesting a distinct lineage fate for this sub-population of T cells. This paper summarizes the current literature relevant to T-cell exhaustion in patients with HBV-related chronic hepatitis, the options for identifying new potential therapeutic targets to treat HBV infection and highlights priorities for further study.
Highlights
Patients with chronic Hepatitis B virus (HBV) infections are usually characterized by a population of exhausted T cells, which have weak virus-specific T-cell responses during chronic HBV infection, impeding the clearance of virus and recovery from hepatitis
Recent efforts have proposed that specific transcription factors such as T-bet were associated with T-cell exhaustion, which were supported by the evidence that T-bet directly repressed transcription of the gene encoding programmed cell death-1 (PD-1), and high T-bet expression sustained exhausted CD8+ T cells in mice infected with LCMV,[23] reminiscent of its role in sustaining exhausted CD4+ T cells.[24]
Significant finding in CHB patients showed that circulating HBV-specific CD8+ T cells were mainly PD-1 positive;[11] in line with those observations in other different viral infections, the exhausted T cells affected by high viral loads would upregulate their expression of PD-1.9,32,33
Summary
Patients with chronic HBV infections are usually characterized by a population of exhausted T cells, which have weak virus-specific T-cell responses during chronic HBV infection, impeding the clearance of virus and recovery from hepatitis.
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