Abstract
The structural maintenance of chromosome 5/6 complex (Smc5/6) is a restriction factor that represses hepatitis B virus (HBV) transcription. HBV counters this restriction by expressing HBV X protein (HBx), which targets Smc5/6 for degradation. However, the mechanism by which Smc5/6 suppresses HBV transcription and how HBx is initially expressed is not known. In this study we characterized viral kinetics and the host response during HBV infection of primary human hepatocytes (PHH) to address these unresolved questions. We determined that Smc5/6 localizes with Nuclear Domain 10 (ND10) in PHH. Co-localization has functional implications since depletion of ND10 structural components alters the nuclear distribution of Smc6 and induces HBV gene expression in the absence of HBx. We also found that HBV infection and replication does not induce a prominent global host transcriptional response in PHH, either shortly after infection when Smc5/6 is present, or at later times post-infection when Smc5/6 has been degraded. Notably, HBV and an HBx-negative virus establish high level infection in PHH without inducing expression of interferon-stimulated genes or production of interferons or other cytokines. Our study also revealed that Smc5/6 is degraded in the majority of infected PHH by the time cccDNA transcription could be detected and that HBx RNA is present in cell culture-derived virus preparations as well as HBV patient plasma. Collectively, these data indicate that Smc5/6 is an intrinsic antiviral restriction factor that suppresses HBV transcription when localized to ND10 without inducing a detectable innate immune response. Our data also suggest that HBx protein may be initially expressed by delivery of extracellular HBx RNA into HBV-infected cells.
Highlights
250 million individuals have chronic hepatitis B (CHB), and more than 780,000 people die each year due to hepatitis B virus (HBV)-associated liver diseases, such as cirrhosis and hepatocellular carcinoma (HCC) [1,2]
In light of this observation, we evaluated whether Smc5 and Smc6 co-localize with components of Nuclear Domain 10 (ND10) in human hepatocytes
While the hepatocyte innate immune response to HBV is poorly understood [34], it was recently demonstrated that HBV closed circular DNA (cccDNA) is transcriptionally silenced by the structural maintenance of chromosome 5/6 complex (Smc5/6) complex when HBV X protein (HBx) is not present [13,35]
Summary
250 million individuals have chronic hepatitis B (CHB), and more than 780,000 people die each year due to HBV-associated liver diseases, such as cirrhosis and hepatocellular carcinoma (HCC) [1,2]. Multiple nucleos(t)ide analogs as well as interferon-α (IFN-α) are approved for the treatment of CHB, but since these therapies rarely lead to cure [3] there is an urgent need to develop novel antiviral therapies. Pharmaceutical targeting of HBx has the potential to transcriptionally silence cccDNA. This would be an attractive therapeutic response since reducing viral antigen levels may restore effective antiviral immunity and drive patients towards functional cure [10]. HBx has been implicated in both the development and progression of HCC [11,12] and so inhibiting HBx function may have potential as a novel therapeutic approach for the prevention and/or treatment of HBV-related HCC
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