Early Multiphasic HBV Infection Initiation Kinetics Is Not Clone-Specific and Is Not Affected by Hepatitis D Virus (HDV) Infection.

Masataka Tsuge,Jeffrey Glenn,Kevin Walsh,Chise Tateno,Kazuaki Chayama,Theo Heller,Christopher Koh,Upendra Kumar,Susan Uprichard,Harel Dahari,Takuro Uchida,Yuji Ishida

doi:10.3390/v11030263

Abstract

Backgrounds and Aims: We previously demonstrated that serum hepatitis B virus (HBV) DNA in HBV infected humanized mice exhibited a highly dynamic multiphasic kinetic pattern from infection initiation to steady-state. Here, we investigated whether this pattern is consistent across different HBV clones or in the presence of hepatitis D virus (HDV) co-infection. Methods: We analyzed early serum viral kinetics using 26 HBV genotype C (GtC) mono-infected mice [clones: PXB, Hiroshima GtC CL4 (CL4) and Hiroshima GtC CL5 (CL5)] and four HBV CL4/HDV genotype one co-infected mice. Results: The HBV kinetics observed with clones CL4 and CL5 were similar to that previously defined in HBV PXB infected mice. Additionally, no significant differences in HBV DNA levels were observed between HBV mono-infected and HBV/HDV co-infected mice through 4 weeks post-inoculation (p.i.). However, HBV DNA levels at 6 weeks p.i. in HBV/HDV co-infected mice were significantly lower than those in HBV mono-infected mice (P = 0.002), consistent with HDV suppression of chronic HBV. Conclusions: HBV infection initiation is multiphasic across multiple viral clones and is not altered by HDV co-infection. The latter suggests that higher HDV titers (>8 log IU/mL) and/or longer duration of HDV infection might be needed to trigger HDV-induced suppression on HBV.

Highlights

We [1] showed that serum hepatitis B virus (HBV) DNA in HBV infected humanized mice exhibited a highly dynamic multiphasic kinetic pattern from infection initiation to steady state.Five of the 7 phases observed occurred within the first 8 days post-inoculation (p.i.) followed by an extended serum HBV DNA amplification phase before steady state was reached between 35–42 days p.i
We examined whether the observed multiphasic HBV kinetic pattern is consistent among different HBV genotype C (GtC) clones and whether co-infection with the hepatitis D virus (HDV), which has been reported to suppress chronic HBV in humans [2] and humanized mice [3], might affect the observed HBV initiation kinetics
The serum containing HDV was inoculated into humanized mice that were already infected with HBV CL4 to generate HBV/HDV superinfected mice with high titers of both HBV

Summary

Introduction

We [1] showed that serum hepatitis B virus (HBV) DNA in HBV infected humanized mice exhibited a highly dynamic multiphasic kinetic pattern from infection initiation to steady state. We examined whether the observed multiphasic HBV kinetic pattern is consistent among different HBV genotype C (GtC) clones and whether co-infection with the hepatitis D virus (HDV), which has been reported to suppress chronic HBV in humans [2] and humanized mice [3], might affect the observed HBV initiation kinetics

Preparation of the Viral Inocula

Human Hepatocyte Chimeric Mouse Experiments

Quantification of Serum HBV DNA

Quantification of serum HDV RNA

Statistical Analyses

Results and Discussions