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Determination of Antiviral Activity
Published in Adorjan Aszalos, Modern Analysis of Antibiotics, 2020
Animal models are beginning to emerge that appear to have great potential as in vivo antiviral evaluative tools for the type B hepatitis virus. The virus will induce an infection in chimpanzees similar to chronic type B hepatitis in humans [108]. This model has been used in antiviral experiments, with negative results that compared well with similarly negative results seen in clinical studies with the same drug [109], Recently, a closely related agent, the woodchuck hepatitis virus, has been isolated that causes moderately severe acute and chronic hepatitis in the woodchuck [110], and another related virus, the ground squirrel hepatitis virus, has been shown to induce a similar disease in the Beechy ground squirrel [111]. A third, somewhat less related virus of note is the duck hepatitis virus, which induces the disease in a variety of ducks [112,113]. Meaningful antiviral experiments with these newly reported hepatitis animal models are yet to be done.
Entecavir
Published in M. Lindsay Grayson, Sara E. Cosgrove, Suzanne M. Crowe, M. Lindsay Grayson, William Hope, James S. McCarthy, John Mills, Johan W. Mouton, David L. Paterson, Kucers’ The Use of Antibiotics, 2017
In a HepG2 cell line stably transfected with HBV the effective concentration of entecavir inhibiting HBV replication by 50% (EC50) was 3.75 ± 1.2nM (mean ± standard deviation), an order of magnitude less than lamivudine (116.3 ± 71.3 nM) (Innaimo et al., 1997). Entecavir was active against both wild-type and lamivudine-resistant HBV mutants, although with the latter strains the EC50 was 30 nM (range: 29–61 nM), resulting in requirement for 20- to 30-fold higher entecavir concentrations to inhibit replication of these strains of HBV in vitro (Levine et al., 2002). The woodchuck hepatitis virus and the duck hepatitis virus are also susceptible to entecavir (Colonno et al., 2001; Marion et al., 2002). Although the drug has a very high barrier to resistance with a stable 1.2% resistance rate after 6 years, this barrier is markedly reduced in cases of preexisting lamivudine resistance due to lamivudine signature resistance mutations containing two of the three mutations necessary for entecavir resistance (Zoulim and Locarnini, 2009).
Viral Infections and Hepatitis
Published in Timothy R. Billiar, Ronald D. Curran, Hepatocyte and Kupffer Cell Interactions, 2017
When a liver biopsy is performed at the beginning of the clinical phase of the disease, an activation of the Kupffer cells is usually reported. The Kupffer cells appear hyperplastic in the space of Disse or even in the sinusoid itself, mingled with circulating macrophages and surrounding affected hepatocytes or cell debris which undergo phagocytosis and digestion.53-56 No current data are available for histological alterations during the preclinical or early phase of the disease in humans. Studies in experimental infection have been carried out with woodchuck hepatitis virus (WHV), one of the hepadnaviruses that is the best analogous animal model for HBV infection.57 At the onset of symptoms, 6 weeks after inoculation, mild lymphocytic and neutrophilic infiltration of the sinusoid was the only histological finding; portal tracts and parenchyma appeared unaffected. At 8 weeks postinoculation, there was a mild hyperplasia of the Kupffer cells adjacent to small foci of degenerative hepatocytes surrounded by lymphocytes, neutrophils, and eosinophils. WHV Ag, as detected by victoria blue, was found in Kupffer cells between 6 and 8 weeks, whereas it was completely undetectable in hepatocytes at that time. In this model, therefore, Kupffer cells appeared as the first hepatic cells infected by the virus. It could be speculated that the sinusoidal inflammation and focal hepatocytic damage are the consequences of Kupffer cell infection and a specific activation, as it has been suggested for about 30 years for various human and animal viral infections.58 At 8 weeks after inoculation, WHV Ag was detectable in the hepatocytes and the classical histological pattern with inflammatory infiltrate and hepatocyte necrosis appeared.
Recent advances in the discovery and development of TLR ligands as novel therapeutics for chronic HBV and HIV infections
Published in Expert Opinion on Drug Discovery, 2018
Keye Du, Jia Liu, Ruth Broering, Xiaoyong Zhang, Dongliang Yang, Ulf Dittmer, Mengji Lu
Increasing evidences showed that HBV can modulate the expression of TLRs and/or inhibit TLR signaling pathways, which might be used by the virus to escape innate immunity [18]. For example, it has been demonstrated that chronic hepatitis B（CHB）patients showed significantly lower levels of TLR1, −2, −4, and −6 expressions in their PBMCs compared with healthy individuals. The PBMCs of CHB patients also produced less cytokines in response to TLR2 and −4 ligand stimulations [35]. The woodchuck hepatitis virus (WHV) and its host, the eastern woodchuck, is a very valuable animal model for HBV infection research. Many aspects of WHV replication and pathogenesis resemble acute and chronic hepatitis B infection in humans [33]. Consistent with findings in HBV-infected patients, downregulation of TLR2 expression in liver tissue and PBMCs was observed in woodchucks chronically infected by woodchuck hepatitis virus (WHV) [31]. Purified HBV virions and viral proteins suppress TLR3 and −4 mediated innate responses in hepatocytes and nonparenchymal liver cells [36]. In line with the observation that reduced innate immune responses are associated with HBV persistence, accumulating evidence has also shown that the activation of the TLRs with their specific ligands is a promising therapeutic strategy against CHB [31,37–40]. The contribution of TLRs to the control of HBV infection is mediated not only by initiating innate antiviral responses, but also by promoting specific adaptive immune responses [41]. The effects of various TLR ligands on the control of HBV infection in different models are summarized in Figure 1.
Recent trends in the development of Toll-like receptor 7/8-targeting therapeutics
Published in Expert Opinion on Drug Discovery, 2021
Xuan Huang, Xiaoyong Zhang, Mengji Lu
GS-9620 is a potent oral TLR7 agonist. In a preclinical study, GS-9620 inhibited prolonged viral replication and led to surface-antigen seroconversion in woodchucks with chronic woodchuck hepatitis virus (WHV) infection [66]. In HBV-infected chimpanzees, single-agent oral therapy with GS-9620 could induce sustained viral suppression in the serum and liver [67]. GS-9620 can also induce the secretion of cytokines and chemokines such as IFN-α, upregulate the expression of TLR7 and interferon-stimulated genes (ISGs) in peripheral blood mononuclear cells (PBMCs) and liver tissue, activate NK-cells and T-cell subpopulations, and initiate an anti-viral immune response, significantly reducing serum levels of HBV DNA and expression of viral antigens [68–70]. It has shown the potential to be curative in animal models; hence, it has been evaluated in patients with chronic HBV infection in a phase-I trial [71]. One or two doses given orally once a week were safe and well tolerated, and were not associated with substantial adverse events. Serum levels of IFN-α were undetectable in 70/80 patients with chronic HBV infection and only a transient increase in ISG15 induction in peripheral blood was observed within 48 h of dosing, followed by a return to baseline levels. Suppressed viral loads were observed in a phase-II trial of GS-9620 in patients with chronic HBV infection undergoing nucleoside/nucleotide analog therapy [72]. The treatment was safe and well tolerated, and was accompanied by dose-dependent induction of ISG15 during ≤12 weeks of treatment. None of the patients exhibited loss of hepatitis B e antigen or hepatitis B surface antigen (HBsAg), though there was a slight decline in HBsAg levels in all cohorts. One possible reason for the minimal decline in HBsAg is that a lack of significant induction of IFN-α expression indicated that TLR7 and cascade reactions were not sufficiently activated in the liver even though the GS-9620 dose was safe and well tolerated. Hence, the effects of monotherapy with GS-9620 were not satisfactory. Another study included patients undergoing suppression of HBV infection via therapy with nucleoside/nucleotide analogs, and they were treated with the same dose of GS-9620 for 12 weeks. There was no decline in serum HBsAg. But GS-9620 enhanced HBV-specific T-cell and NK-cell responses, and even reduced the capacity of NK-cells to suppress T-cells [73]. The disappointing results of clinical trials suggest that a deeper understanding of the mechanism of action of TLR7 agonists is needed. In an in vitro study, it was concluded that GS-9620 could not have activated antiviral pathways in human hepatocytes directly. It could suppress HBV DNA and HBV antigen via the induction of multiple cytokines, particularly IFNs, and its activation of immune cells also had an important role in the antiviral response [68].