Identification of Therapeutic Targets for the Selective Killing of HBV-Positive Hepatocytes.

Chien Jung Huang ,Lily Wang ,Yu Chao Wang

doi:10.3390/jpm11070649

Abstract

The hepatitis B virus (HBV) infection is a major risk factor for cirrhosis and hepatocellular carcinoma. Most infected individuals become lifelong carriers of HBV as the drugs currently used to treat the patients can only control the disease, thereby achieving functional cure (loss of the hepatitis B surface antigen) but not complete cure (elimination of infected hepatocytes). Therefore, we aimed to identify the target genes for the selective killing of HBV-positive hepatocytes to develop a novel therapy for the treatment of HBV infection. Our strategy was to recognize the conditionally essential genes that are essential for the survival of HBV-positive hepatocytes, but non-essential for the HBV-negative hepatocytes. Using microarray gene expression data curated from the Gene Expression Omnibus database and the known essential genes from the Online GEne Essentiality database, we used two approaches, comprising the random walk with restart algorithm and the support vector machine approach, to determine the potential targets for the selective killing of HBV-positive hepatocytes. The final candidate genes list obtained using these two approaches consisted of 36 target genes, which may be conditionally essential for the cell survival of HBV-positive hepatocytes; however, this requires further experimental validation. Therefore, the genes identified in this study can be used as potential drug targets to develop novel therapeutic strategies for the treatment of HBV, and may ultimately help in achieving the elusive goal of a complete cure for hepatitis B.

Highlights

Hepatitis B virus (HBV) is a double-stranded DNA virus and a member of the familyHepadnaviridae
Using the microarray gene expression profiles for HBV(+) and HBV(−) samples downloaded from the GEO database, a computational framework was developed to predict the conditionally essential genes (CEGs)
The results show that the correlation between the identified overlapping candidate genes and known essential genes is higher in HBV(+) samples, but lower in HBV(−) samples, which means that the 36 overlapping candidate genes are more likely to be essential genes in HBV(+) samples, but not in HBV(−) samples

Summary

Introduction

Hepatitis B virus (HBV) is a double-stranded DNA virus and a member of the familyHepadnaviridae. Based on the transmission of HBV, this infection can be divided into blood and body fluid infections, and the mode of infections can further be divided into vertical and horizontal infections. As vertical infection is the main source of infection, Taiwan has been administering the hepatitis B vaccine since 1984. The vaccination program has effectively blocked the vertical infection of hepatitis B, and the prevalence of hepatitis B among those younger than 20 years old decreased from 9.8% in 1984 to 0.6% in 2004 [3]. Even if the hepatitis B vaccine is effective, most infected individuals will become lifelong carriers of HBV as there is no cure for HBV infection. There are two types of agents available for the treatment of HBV infection: interferons and nucleotide analogs

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