Activity of nucleic acid polymers in rodent models of HBV infection

Katrin Schöneweis,Neil Motter,Pia L Roppert,Mengji Lu,Baoju Wang,Ingo Roehl,Dieter Glebe,Dongliang Yang,John D Morrey,Michael Roggendorf,Andrew Vaillant

doi:10.1016/j.antiviral.2017.10.022

Abstract

Nucleic acid polymers (NAPs) block the release of HBsAg from infected hepatocytes. These compounds have been previously shown to have the unique ability to eliminate serum surface antigen in DHBV-infected Pekin ducks and achieve multilog reduction of HBsAg or HBsAg loss in patients with chronic HBV infection and HBV/HDV coinfection. In ducks and humans, the blockage of HBsAg release by NAPs occurs by the selective targeting of the assembly and/or secretion of subviral particles (SVPs).The clinically active NAP species REP 2055 and REP 2139 were investigated in other relevant animal models of HBV infection including woodchucks chronically infected with WHV, HBV transgenic mice and HBV infected SCID-Hu mice. The liver accumulation of REP 2139 in woodchucks following subcutaneous administration was examined and was found to be similar to that observed in mice and ducks. However, in woodchucks, NAP treatment was associated with only mild (36–79% relative to baseline) reductions in WHsAg (4/10 animals) after 3–5 weeks of treatment without changes in serum WHV DNA. In HBV infected SCID-Hu mice, REP 2055 treatment was not associated with any reduction of HBsAg, HBeAg or HBV DNA in the serum after 28 days of treatment. In HBV transgenic mice, no reductions in serum HBsAg were observed with REP 2139 with up to 12 weeks of treatment.In conclusion, the antiviral effects of NAPs in DHBV infected ducks and patients with chronic HBV infection were weak or absent in woodchuck and mouse models despite similar liver accumulation of NAPs in all these species, suggesting that the mechanisms of SVP assembly and or secretion present in rodent models differs from that in DHBV and chronic HBV infections.

Highlights

Several models of hepadnaviral infection have been established to investigate the viral replication and pathogenesis of HBV infection in humans (Dandri and Petersen, 2017; Innacone and Guidotti, 2015)
Natural woodchuck hepatitis virus (WHV) or duck hepatitis B virus (DHBV) infection in woodchucks and ducks respectively results in an abundant excess of circulating surface antigen derived from subviral particles (SVP) (Franke et al, 2007; Summers et al, 1978) similar to that observed in HBV infection (Chai et al, 2008)
The clearance of DHBsAg during Nucleic acid polymers (NAPs) therapy is accompanied by clearance of DHBV DNA from the blood and reduced viral replication in the liver (Roehl et al, 2017), an effect which persists after treatment was withdrawn and was accompanied by the absence of detectable DHBcAg, DHBsAg, and multilog reduction of cccDNA in the liver (Noordeen et al, 2015; Quinet et al, 2016)

Summary

Introduction

Several models of hepadnaviral infection have been established to investigate the viral replication and pathogenesis of HBV infection in humans (Dandri and Petersen, 2017; Innacone and Guidotti, 2015). In established DHBV infection, the post-entry activity of the NAPs REP 2055 and REP 2139 resulted in the reduction of DHBsAg after one week of treatment with clearance of serum DHBsAg achieved as soon as two weeks after the start of treatment (Noordeen et al, 2015; Quinet et al, 2016) This antiviral effect was shown to result from the inhibition of release of DHBsAg from the liver, an effect apparently driven by the inhibition of SVP assembly and/or release (Noordeen et al, 2015). The clearance of DHBsAg during NAP therapy is accompanied by clearance of DHBV DNA from the blood and reduced viral replication in the liver (Roehl et al, 2017), an effect which persists after treatment was withdrawn and was accompanied by the absence of detectable DHBcAg, DHBsAg, and multilog reduction of cccDNA in the liver (Noordeen et al, 2015; Quinet et al, 2016)

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Discussion

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