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The Contribution of Cell Division to HBV Resolution
Immune cells have the ability to destroy the cccDNA together with the infected cell, as well as to induce com
pensatory hepatocyte proliferation.79,80 Previous studies performed in animal models based on hepadnaviruses and their natural hosts (ducks and woodchucks),71,81 as well as using patient liver biopsies,82 indicated an inverse relationship between cell turnover and intrahepatic cccDNA loads. Furthermore, cccDNA-negative cell clones containing HBV DNA integrations into the host genome demonstrated that cccDNA clearance without cell
tion can occur in chronically infected livers.83
The cccDNA is an episomal, plasmid-like, structure lacking centromeres. Reports indicated that cell division may lead to an equal84 or unequal distribution of the cccDNA molecules among daughter cells or even cause their loss during mitosis85 (Figure 1). In fact, cytosolic nucleases may promote efficient destruction of DNA mole
cules that are released into the cytoplasm.86 Recent studies in human liver chimeric mice showed that the proliferation of HBV-infected human hepatocytes provoked a strong reduction of intrahepatic cccDNA loads.66 Moreover, cell division caused not only dilution of the HBV cccDNA among daughter cells but also a substantial loss of
patic cccDNA amounts. In spite of the fact that cccDNA could be efficiently purged from the great majority of the human hepatocytes, complete viral clearance was not achieved since HBV survived in sporadic, apparently non- proliferating human hepatocytes.66 Consequently,
cal markers rebounded as hepatocyte expansion relented and such rebound was largely due to reinfection of
cent primary human hepatocytes, since treatment with the entry inhibitor Myrcludex-B blocked viral spread and
intrahepatic cccDNA accumulation. The persistence of very few dispersed non-proliferating hepatocytes expressing high levels of HBV markers (HBcAg and HBV RNA) indicated that viral infection might hamper cell division. This observation is in line with previous studies pointing out the lower capacity of hepatocytes to proliferate in HBV- transgenic mice during liver regeneration.87 The lower abil
ity of HBV-positive cells to undergo mitosis might have significant clinical implications, since cells unable or that are less prone to divide may serve as viral reservoir. These experimental observations suggest that the development of therapeutic interventions targeting such persisting HBV- producing cells may be critical to achieve viral elimination. Moreover, the impact of cell division on cccDNA
nance suggests that curative therapeutic approaches may need the involvement of controlled destruction of infected cells, for instance by boosting HBV-specific immune responses, whereas strategies preventing occurrence of new infection events would protect cured hepatocytes from re-infection. In this regard, an attractive strategy
ing at restoring viral immune responses may rely on the adaptive transfer of engineered HBV-specific T cells. Recent studies have shown how T cells expressing an HBV- specific T cell receptor (TCR) can specifically target HBV- infected hepatocytes both in vitro and in vivo, leading to significant elimination and perhaps also silencing of the cccDNA.88–90
In sum, increasing lines of evidence support the concept that both killing of infected cells and compensatory prolif
eration play a key synergistic role in resolving HBV
tion. The fast recovery from acute HBV infection in adult patients suggests that multiple factors, including cytolytic cell killing and non-cytolytic mechanisms, such as
satory hepatocyte proliferation and cytokine-mediated destabilization of the cccDNA (see section Impact of
viral treatments on the cccDNA – interferons), contribute to HBV clinical resolution with loss of HBsAg while the liver remains functional. Such synergistic processes might also be active in
CHB patients that stopped long-term NA
apy before reaching loss of HBsAg and that were reported to achieve a more favorable treatment outcome after
encing a transitory hepatic flare.75,91,92 Notably, reports indicated that low cccDNA amounts can be detected even in the liver of patients that resolved acute HBV infection,78 thus augmenting the assumption that we may not need to eliminate the intrahepatic cccDNA reservoir completely in order to gain sustained off-treatment control resembling natural resolution of HBV infection. |
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发表于 2020-11-6 12:34