Host–virus interactions in hepatitis B virus infection
Introduction
Hepatitis B virus (HBV) is a small, circular, hepatotropic dsDNA virus that causes acute and chronic hepatitis and hepatocellular carcinoma [1•]. Our understanding of the host–virus interactions that determine the outcome of HBV infection reflects the results of studies conducted in naturally infected humans, experimentally infected chimpanzees, surrogate animal models (e.g. woodchucks and ducks infected by closely related hepadnaviruses and transgenic mice supporting HBV gene expression and replication) and assorted cell culture systems that support some or all aspects of the HBV life cycle in vitro [1•].
It is generally acknowledged that hepatocellular HBV infection is noncytopathic, that it does not trigger innate immune responses readily measurable in vivo [2], and that robust, polyclonal and multispecific CD4+ and CD8+ T cell responses and neutralizing antibody responses contribute to the resolution of HBV infection. CD4+ T cells facilitate induction and maintenance of both CD8+ T cells and neutralizing antibodies [3]. CD8+ T cells kill infected cells and secrete antiviral cytokines (mainly interferon [IFN]-γ) that inhibit HBV replication noncytopathically [4, 5]. Neutralizing antibodies limit viral spread from residual productively infected hepatocytes that are not eliminated by the CD8+ T cells [6]. The virus persists in the majority of neonatal/perinatal infections and a small minority of adult onset infections, reflecting the failure of one or more of these aspects of the immune response and mutational escape from immune recognition; and it secondarily triggers an indolent low grade chronic necroinflammatory liver disease that can progress to hepatocellular carcinoma (HCC) [4, 7]. Vaccines that elicit neutralizing antibodies to hepatitis B surface antigen (HBsAg) efficiently prevent de novo HBV infection [8], but have no therapeutic potential for the ∼240 million people that are persistently infected with this virus worldwide [9]. Therapy for these individuals mainly relies on direct acting antiviral (DAA) drugs that suppress virus production but do not eradicate HBV from the liver, requiring lifelong treatment [10]. Importantly, chronic HBV infection spontaneously resolves in a small fraction of patients, usually concomitant with functional restoration of adaptive immunity to HBV [11, 12•].
Despite these advances, important aspects of HBV immunobiology and pathogenesis remain ill defined, especially the immunological mechanisms responsible for viral persistence. A more complete understanding of these mechanisms is needed before immunotherapeutic strategies to cure chronic HBV infection can be rationally developed.
Section snippets
Understanding the role of innate immunity in HBV infection
Studies in acutely infected chimpanzees have shown that IFN-α/β, IFN-λ, IFN-γ and IFN-stimulated genes [ISGs] are not measurably induced during the initial spread of HBV throughout the liver (i.e. before the arrival of T cells) [2, 13], indicating that HBV replicates noncytopathically and remains largely undetected by the infected hepatocytes or by intrahepatic innate immune cells such as NK and NKT cells.
Recently, Sato et al. showed that (i) low levels of IFN-λ and selected ISGs are
Understanding the role of adaptive immunity in HBV infection
As mentioned earlier, adaptive immune responses, particularly the HBV-specific CD8+ T cell response, play a key role in viral clearance and disease pathogenesis. Hence the failure to prime, expand or differentiate an effector memory T cell response to HBV or effective evasion of that response could be responsible for viral persistence.
Both viral and host factors are thought to contribute to HBV persistence. Viral factors include the possibility that circulating hepatitis B e-antigen (HBeAg)
Concluding remarks
Based on the evidence summarized herein, it is clear that continuing analysis of the host–virus interactions that determine the outcome of HBV infection is needed if we are to develop curative strategies for chronic HBV infection. Relevant to this, it is important to point out that a cure for HBV requires that the covalently closed circular (ccc) DNA, the HBV transcriptional template in the nucleus of infected hepatocytes [1•], must be eliminated, which almost never occurs after DAA treatment [
References and recommended reading
Papers of particular interest, published within the period of review, have been highlighted as:
• of special interest
•• of outstanding interest
Acknowledgements
This work was supported by grants: 250219 (LGG) from the European Research Council (ERC), KAKENHI 26461015 (MI) from JSPS, and Research Program on Hepatitis (MI) from AMED, and R01-AI-020001 and R01-CA-040489 (FVC) from the NIH.
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