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  • Zinc protoporphyrin IX In summary we propose a model that

    2021-10-16

    In summary, we propose a model that explains the possible mechanism the HULC mediates activation of HBV in liver cancer Zinc protoporphyrin IX (Fig. 8). In the model, HULC promotes the expression of miR-539 by stimulating HBx-co-activated STAT3. Then, miR-539 down-regulates APOBEC3B, leading to an increase of HBV cccDNA, which acts as a template for HBV replication. Thus, HULC activates HBV replication by HBx/STAT3/miR-539/APOBEC3B signaling, leading to the growth of liver cancer. Our finding provides new insights into the mechanism by which HULC promotes HBV in hepatocarcinogenesis.
    Conflicts of interest
    Introduction Hepatitis B virus (HBV) is a major global health problem. An estimated 257 million people are chronically infected worldwide, resulting in >880,000 deaths annually from HBV-associated liver diseases, including cirrhosis, hepatocellular carcinoma, and liver failure (WHO, 2017). HBV-associated health care costs are up to $39,898 per quality-adjusted life year (Xie et al., 2018). Available anti-HBV therapies are limited to two forms of the innate immunity cytokine interferon-α and six Zinc protoporphyrin IX nucleoside/nucleotide analogs (NA) which block DNA chain elongation by the viral polymerase. These therapies significantly improve patient outcomes, and NA can suppress viremia by more than 4–5 log10 in the majority of patients (Cox and Tillmann, 2011; Kwon and Lok, 2011). However, HBV replication still persists in most patients, therefore these therapies must be continued indefinitely (Coffin et al., 2011; Zoulim, 2004). It is widely accepted that curing HBV will require new drugs against new targets capable of further suppressing HBV (Petersen et al., 2016). These new therapies will need to work together with other anti-HBV treatments, be well tolerated during prolonged use, and have a high genetic barrier to resistance. We are exploring the HBV ribonuclease H (RNaseH) as an antiviral drug target. The RNaseH is one of two enzymatically active domains on the HBV polymerase that synthesizes the partially double-stranded DNA genome via reverse transcription. The reverse transcriptase (RT) domain of the polymerase protein copies the pregenomic RNA (pgRNA) template to form the minus-polarity DNA strand. The RNaseH recognizes RNA:DNA heteroduplexes that are formed during minus-polarity DNA synthesis and degrades the RNA strand (Seeger et al., 2013; Tavis and Badtke, 2009). The polymerase then synthesizes the positive-polarity DNA strand, but it typically arrests after making only ∼50% of the plus-polarity DNA strand. Both enzymatic activities of the polymerase are required for synthesis of the HBV genome, yet the RNaseH is an unexploited drug target (Tavis and Lomonosova, 2015). Blocking the HBV RNaseH activity prevents removal of the RNA strand from the minus–polarity DNA strand, resulting in an accumulation of RNA:DNA heteroduplexes (Hu et al., 2013). Failure to remove the pgRNA blocks synthesis of positive-polarity DNAs and causes premature arrest of minus-polarity DNA synthesis (Edwards et al., 2017; Gerelsaikhan et al., 1996; Hu et al., 2013; Tavis et al., 2013), with truncation of the minus-polarity DNAs possibly stemming from conformational constraints imposed on the viral DNA within capsids due to accumulation of the heteroduplexes. This prevents the formation of a complete viral genome, thus stopping both transmission of infectious viral particles and the intracellular “recycling” mechanism that replenishes the pool of covalently closed circular DNA (cccDNA), the template for all HBV RNAs. We recently developed an HBV RNaseH screening pipeline (Cai et al., 2014; Edwards et al., 2017; Hu et al., 2013; Lomonosova et al., 2017a, 2017b; Lu et al., 2015, 2016; Tavis et al., 2013; Tavis and Lomonosova, 2015). We identified >100 inhibitors primarily in three compound classes, the α-hydroxytropolones (αHT), N-hydroxyisoquinolinediones (HID), and N-hydroxypyridinediones (HPD), that suppress viral replication in cells by blocking the HBV RNaseH. These compounds preferentially suppress the plus-polarity DNA strands, induce truncation of the minus-polarity DNA strands, and cause accumulation of extensive RNA:DNA heteroduplexes in capsids as expected from their inhibition of the RNaseH. The best compounds have therapeutic indexes [cytotoxicity/efficacy (TI)] >200 (Lomonosova et al., 2017a). Representative HBV RNaseH inhibitors can work synergistically with approved and experimental therapies (Lomonosova et al., 2017b), inhibit multiple HBV isolates from genotypes B, C, and D equivalently (Lu et al., 2016), and suppress viral replication in a chimeric mouse model (Long et al., 2018). Therefore, the HBV RNaseH is a validated drug target.