GS-9620, an Oral Agonist of Toll-Like Receptor-7, Induces Prolonged Suppression of Hepatitis B Virus in Chronically Infected Chimpanzees

Lanford, Robert E.; Guerra, Bernadette; Chavez, Deborah J.; Giavedoni, Luis D.; Hodara, Vida; Brasky, Kathleen M.; Fosdick, Abigail; Frey, Christian; Zheng, Jim; Wolfgang, Grushenka H.I.; Halcomb, Randall L.; Tumas, Daniel B.

doi:10.1053/j.gastro.2013.02.003

Cited by 341 publications

(300 citation statements)

References 34 publications

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“…Recently, oral TLR7 ligands successfully induced viral control in Woodchuck and chimpanzee HBV-animal models (Menne et al, 2015;Lanford et al, 2013). Disappointingly in humans, oral TLR7 ligands thus far have not achieved any beneficial effect, despite that treatment was well tolerated (Gane et al, 2015;Janssen et al, 2017).…”

Section: Discussionmentioning

confidence: 99%

TLR7 polymorphism, sex and chronic HBV infection influence plasmacytoid DC maturation by TLR7 ligands

et al. 2018

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A B S T R A C TTLR7 agonists are of high interest for the treatment of cancer, auto-immunity and chronic viral infections. They are known to activate plasmacytoid dendritic cells (pDCs) to produce high amounts of Type I Interferon (IFN) and to facilitate T and B cell responses, the latter with the help of maturation markers such as CD40, CD80 and CD86. The TLR7 single nucleotide polymorphism (SNP) rs179008 (GLn11Leu), sex and chronic viral infection have all been reported to influence pDC IFN production. It is unknown, however, whether these factors also influence pDC phenotypic maturation and thereby IFN-independent pDC functions. Furthermore, it is unclear whether SNP rs179008 influences HBV susceptibility and/or clearance.Here we investigated whether the SNP rs179008, sex and HBV infection affected phenotypic maturation of pDCs from 38 healthy individuals and 28 chronic HBV patients. In addition, we assessed SNP prevalence in a large cohort of healthy individuals (n = 231) and chronic HBV patients (n = 1054).Consistent with previous reports, the rs179008 variant allele was largely absent in Asians and more prevalent in Caucasians. Among Caucasians, the SNP was equally prevalent in healthy and chronically infected males. The SNP was, however, significantly more prevalent in healthy females than in those with chronic HBV infection (42 versus 28%), suggesting that in females it may offer protection from chronic infection. Ex vivo experiments demonstrated that induction of the co-stimulatory molecules CD40 and CD86 by TLR7 ligands, but not TLR9 ligands, was augmented in pDCs from healthy SNP-carrying females. Furthermore, CD80 and CD86 upregulation was more pronounced in females independent of the SNP. Lastly, our data suggested that chronic HBV infection impairs pDC maturation. These findings provide insight into factors determining TLR7 responses, which is important for further clinical development of TLR7-based therapies.

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Section: Discussionmentioning

confidence: 99%

TLR7 polymorphism, sex and chronic HBV infection influence plasmacytoid DC maturation by TLR7 ligands

et al. 2018

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“…Therefore, they have the potential to influence the nature of innate immune responses during infection and are a primary target of new synthetic Toll-like receptor(TLR)-based antivirals. 20 Similar to mDCs, the majority of studies have found that the frequency of pDCs was similar between chronic HBV patients and healthy donors (Table 2). 14-17,21-23 As noted above for mDCs, this result was consistent for adults, pediatric patients 12 and infants born to HBV-positive mothers.…”

Section: Overviewmentioning

confidence: 91%

Dissecting the dendritic cell controversy in chronic hepatitis B virus infection

Gehring

D’Angelo

2014

Cell Mol Immunol

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Therapeutic vaccines to boost endogenous T-cell immunity rely on the stimulatory capacity of dendritic cells (DCs). The functionality of DCs in chronic hepatitis B virus (HBV) infection has been a long-standing debate. Therefore, we have attempted to summarize multiple studies investigating DC function in chronic HBV patients to determine whether common observations can be drawn. We found that the frequency and function of ex vivo-tested myeloid and plasmacytoid DCs were largely intact in patients with HBV infection and similar to those of healthy donor DCs. The main exception was reduced IFN-a production by plasmacytoid DC from chronic HBV patients. This reduced IFN-a production correlated with liver inflammation in multiple studies but not with viral load, suggesting that viral antigens have little effect on DC function. The majority of the confusion about DC function arises from studies reporting the reduced function of healthy donor DCs exposed to various sources of HBV in vitro. These direct effects of viral antigens are in contrast to data from HBV-infected patients. The variations in the assays used and areas that require further investigation are also covered

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“…T cells [51]. TLR7 agonist administered orally to chimpanzees was observed to stimulate IFN-a production and the activation of ISGs and NK cells, resulting in prolonged suppression of HBV [52]. Blockade of programmed cell death (PD)-1 protein is an alternative and promising approach in chronic HBV infection.…”

Section: Immunological Intervention Against Hbv Infectionmentioning

confidence: 99%

Host–virus interactions in hepatitis B and hepatitis C infection

Yoshio

Kanto

2016

J Gastroenterol

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Hepatitis B virus (HBV) and hepatitis C virus (HCV) are among the most endemic pathogens worldwide, with more than 500 million people globally currently infected with these viruses. These pathogens can cause acute and chronic hepatitis that progress to liver cirrhosis or hepatocellular carcinoma. Both viruses utilize multifaceted strategies to evade the host surveillance system and fall below the immunological radar. HBV has developed specific strategies to evade recognition by the innate immune system and is acknowledged to be a stealth virus. However, extensive research has revealed that HBV is recognized by dendritic cells (DCs) and natural killer (NK) cells. Indoleamine-2, 3-dioxygenase is an enforcer of sequential immune reactions in acute hepatitis B, and this molecule has been shown to be induced by the interaction of HBV-infected hepatocytes, DCs, and NK cells. The interleukin-28B genotype has been reported to influence HCV eradication either therapeutically or spontaneously, but the biological function of its gene product, a type-III interferon (IFN-k3), remains to be elucidated. Human BDCA3 ? DCs have also been shown to be a potent producer of IFN-k3 in HCV infection, suggesting the possibility that BDCA3 ? DCs could play a key role in developing therapeutic HCV vaccine. Here we review the current state of research on immune responses against HBV and HCV infection, with a specific focus on innate immunity. A comprehensive study based on clinical samples is urgently needed to improve our understanding of the immune mechanisms associated with viral control and thus to develop novel immune modulatory therapies to cure chronic HBV and HCV infection.

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GS-9620, an Oral Agonist of Toll-Like Receptor-7, Induces Prolonged Suppression of Hepatitis B Virus in Chronically Infected Chimpanzees

Cited by 341 publications

References 34 publications

TLR7 polymorphism, sex and chronic HBV infection influence plasmacytoid DC maturation by TLR7 ligands

TLR7 polymorphism, sex and chronic HBV infection influence plasmacytoid DC maturation by TLR7 ligands

Dissecting the dendritic cell controversy in chronic hepatitis B virus infection

Host–virus interactions in hepatitis B and hepatitis C infection

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