Researchers Map Genetic Interaction Between HCV and Infected Hosts

How does the genome of the hepatitis C virus (HCV) interact with that of the infected host? That is what researchers at the University of Oxford set out to investigate in a study published in Nature Genetics.

According to the first Global Hepatitis Report, published by the World Health Organization (WHO) earlier this month, there were 68 million people living with chronic HCV infection worldwide in 2015; WHO estimates that this number reached 71 million in 2017. In addition, WHO reports that an estimated 399,000 individuals with chronic HCV die as a result of liver complications associated with the viral disease on an annual basis.

Currently, there is no vaccine to prevent HCV; therefore, many of those who reside in HCV-endemic regions must rely on other modes of infection prevention, such as proper hand hygiene, condom use, and avoiding needle sharing, to protect themselves from infection.

“Outcomes of HCV infection and treatment depend on viral and host genetic factors,” the researchers wrote in their study. However, not much is known about how the genetic makeup of the virus impacts infected individuals, at least, until now. The research team, led by Professor Ellie Barnes, PhD, Nuffield Department of Medicine, and Chris Spencer, PhD, Wellcome Trust Centre for Human Genetics, recently conducted the first “big-data study” to investigate the genetic interaction between HCV and the host.

The researchers used “human genome-wide genotyping arrays and new whole-genome HCV viral sequencing technologies to perform a systemic genome-to-genome study of 542 individuals who were chronically infected with HCV, predominantly genotype 3,” as well as with genotype 2.

When discussing the study with the University of Oxford news department, Dr. Barnes said, “We identified two places in the human genome where the genetic variation that calibrates our immune system affects the genetic diversity of the virus.”

According to the study results, “both alleles of genes encoding human leukocyte antigen molecules and genes encoding components of the interferon lambda innate immune system drive viral polymorphism.” In addition, “We show that an interaction between host IFNL4 genotypes and an amino acid residue in the HCV NS5A protein determines HCV viral load.”

So why is this important? Although advancements in HCV treatment have been made in the last several years, antivirals remain scarce and expensive for many individuals around the world. In fact, Doctors without Borders, along with around 30 other organizations from 17 European countries, recently challenged an HCV drug patent held by Gilead Sciences Inc. in Europe, in an effort to increase access to treatment. Even so, many of the HCV antivirals available on the market are not equally effective in treating all HCV genotypes, which emphasizes “the importance of understanding the genetic basis of the disease for developing future treatments.”

“By assessing viral evolution in individuals with different IFNL4 genotypes, we highlight systematic differences in the innate immune response and discuss how these might relate to previous associations with spontaneous clearance and clinical treatment,” the researchers write.

Although this study is one of the first of its kind conducted on such a large cohort, the researchers believe that, “within 15 years, DNA sequencing of disease-causing bugs like HCV will become a routine part of healthcare.”

This study is part of the STOP-HCV consortium, which is led by University of Oxford and funded by the Medical Research Council. The aim of the consortium is to understand HCV and infection with the virus on a biological level, and from there improve treatment options.