Highlights CXCR5 + CD8 + T cells produce higher levels of HBV-specific IFN-c and IL-21 than CXCR5 À CD8 + T cells. CXCR5 + CD8 + T cells retain functional capacity in inhibiting HBV replication and supporting B cell antibody production. PD1 blockade and exogenous IL-21 enhance production of IFN-c from CXCR5 + CD8 + T cells. High expression of intrahepatic CXCL13 facilitates CXCR5 +-CD8 + T cell recruitment and promotes immune control of HBV.
Carnosine (β-alanyl-L-histidine), described as an enigmatic peptide for its antioxidant, anti-aging and especially antiproliferation properties, has been demonstrated to play an anti-tumorigenic role in certain types of cancer. However, its function in human gastric carcinoma remains unclear. In this study, the effect of carnosine on cell proliferation and its underlying mechanisms were investigated in the cultured human gastric carcinoma cells. The mTOR signaling axis molecules were analyzed in carnosine treated cells. The results showed that treatment with carnosine led to proliferation inhibition, cell cycle arrest in the G0/G1 phase, apoptosis increase, and inhibition of mTOR signaling activation by decreasing the phosphorylation of Akt, mTOR and p70S6K, suggesting that proliferation inhibition of carnosine in human gastric carcinoma was through the inhibition of Akt/mTOR/p70S6K pathway, and carnosine would be a mimic of rapamycin.
A round 400 million people worldwide are infected with hepatitis B virus (HBV). Chronic hepatitis B (CHB), which is triggered by HBV infection, results in a huge health burden on the global community, as it is correlated with a significantly increased risk for the development of cirrhosis, liver failure, and hepatocellular carcinoma (HCC) (1). Currently, treatment of CHB consists mainly of pegylated alpha interferon (IFN-␣) and nucleoside or nucleotide analogs (e.g., lamivudine, adefovir, and entecavir). IFN-␣ was the first drug licensed to treat HBV infection. As an important first-line treatment option, pegylated IFN-␣ as monotherapy can effectively treat CHB in 25 to 40% of patients, and greater sustained virological responses (SVRs) and hepatitis B virus e antigen (HBeAg) seroconversion rates in HBeAg-positive patients were observed with addition of nucleoside/nucleotide analogue therapies (2, 3). In fact, treatment with pegylated IFN results in the highest rate of off-treatment sustained responses among currently available drugs (4). Moreover, responses to IFNbased therapy are accompanied by the potential for hepatitis B virus surface antigen (HBsAg) loss or seroconversion, and early serum HBsAg loss was recently reported to have predictive value for SVRs to IFN in both HBeAg-positive and -negative CHB patients (5-7).As a member of the type I interferons, IFN-␣ can initiate the activation of Jak/STAT and NF-B signaling, which induces hundreds of IFN-stimulated genes (ISGs) and may play an important role in IFN-mediated anti-HBV activity. Both in vitro and in vivo studies have shown that besides a stimulating effect on cytotoxic T lymphocytes and natural killer cell function, IFN-based therapy (IFN-␣-2b and pegylated IFN-␣-2a or -2b) also has a direct antiviral effect by preventing the formation or accelerating decay of viral capsids and/or inducing antiviral ISGs that inhibit HBV expression and replication (8-13). Inhibition of IFN-␣ signaling by HBV has been suggested to antagonize the IFN response (14).Nevertheless, these studies also strongly suggest that there is significant potential, in principle, to modulate the effectiveness of IFN-mediated anti-HBV activities. Moreover, the antiviral activity of ISGs remains elusive and still awaits further investigation (15). Responses to IFN-␣ therapy vary greatly in CHB patients, but the underlying mechanisms are almost unknown (4-6). Notably, IFN-␣/ was recently found to suppress HBV replication in HBV transgenic mice when the viral load was high, whereas it enhanced HBV replication when the viral load was low, indicating its dual function for HBV (16). Taken together, the data show that the precise mechanism of action of IFN-␣ has not been understood fully.MicroRNAs (miRNAs) are a class of small RNAs of approximately 22 nucleotides (nt) which interact with complementary target sites, usually in the 3=-untranslated region (3=-UTR) of target mRNAs, and induce their translational repression, deadenylation, and degradation. MicroRNA-122 (miR-122), a mammalian liv...
Chronic hepatitis B infection remains incurable because HBV cccDNA can persist indefinitely in patients recovering from acute HBV infection. Given the incidence of HBV infection and the shortcomings of current therapeutic options, a novel antiviral strategy is urgently needed. To inactivate HBV replication and destroy the HBV genome, we employed genome editing tool CRISPR/Cas9. Specifically, we found a CRISPR/Cas9 system (gRNA-S4) that effectively targeted the HBsAg region and could suppress efficiently viral replication with minimal off-target effects and impact on cell viability. The mutation mediated by CRISPR/Cas9 in HBV DNA both in a stable HBV-producing cell line and in HBV transgenic mice had been confirmed and evaluated using deep sequencing. In addition, we demonstrated the reduction of HBV replication was caused by the mutation of S4 site through three S4 region-mutated monoclonal cells. Besides, the gRNA-S4 system could also reduce serum surface-antigen levels by 99.91 ± 0.05% and lowered serum HBV DNA level below the negative threshold in the HBV hydrodynamics mouse model. Together, these findings indicate that the S4 region may be an ideal target for the development of innovative therapies against HBV infection using CRISPR/Cas9.
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