The secret of viral drug resistance

Scientists at Trinity College Dublin have discovered a secret that may explain why some people are able to fight viral infections
.
They screened
the immune systems of women who had been exposed to hepatitis C (HCV) through contaminated anti-hepatitis D (HCV) transfusions in Ireland more than 40 years ago.

This remarkable research, just published in the leading journal Cell Reports Medicine, has broad implications
from improving our fundamental understanding of viral drug resistance to potential therapeutics to treat infected people.

Between 1977 and 1979, thousands of women in Ireland were exposed to the hepatitis C virus
through contaminated anti-D antibodies.
Anti-D antibodies are drugs made from plasma from donated blood and given to Ganges-negative women in rhesus-positive fetuses
.
This medicine prevents the production of antibodies, which can be dangerous
in later pregnancies.
Some anti-D drugs used in 1977-79 were contaminated with hepatitis C
.

From this outbreak, three categories of people can be identified: chronically infected people; Those who clear the infection by antibody reaction; and those who
do not appear to have produced antibodies to hepatitis C and are not infected.

Cliona O'Farrelly, professor of comparative immunology in the School of Biochemistry and Immunology at Trinity College, is the senior author
of the research article.
Cliona, who works at the Trinity Institute of Biomedical Sciences, said:

"We hypothesized that women who appear to be able to resist hepatitis C virus infection must have an enhanced innate immune response, which is an ancient part of the immune system that acts as the first line
of defense.
To verify this, we need to reach out to women who were exposed to the virus more than 40 years ago and ask them to help us study their immune systems for scientific clues that explain their different responses
.
After a nationwide campaign in which more than 100 women came forward, we gained some unique and important insights
.
The willingness of so many women – many of whom suffer from long-term complications – to help is a testament to how much people want to get involved in science and help engage in research
that has the potential to have a real positive impact on society.
We are deeply grateful to
them.
The scientists eventually recruited nearly 40 women from the drug-resistant group, as well as 90 women
who had previously been infected.
In collaboration with the Institut Pasteur in Paris, they invited nearly 20 women in each group to donate a blood sample, which was then stimulated with molecules that mimic viral infections, thereby activating the innate immune system
.

Jamie Sugrue, a doctoral student in the School of Biochemistry and Immunology at Trinity College, is the first author
of the research paper.
"By comparing the responses of drug-resistant women and infected women, we found that drug-resistant donors had an enhanced type I interferon response
after stimulation," he said.
Type I interferons are a key family of antiviral immune mediators and play an important role
in defending against viruses including hepatitis C and SARS-CoV-2 (or COVID-19).
We believe that the increase in type I interferon production by our drug-resistant donors, nearly 40 years after initial exposure to hepatitis C, is what protects
them from infection.
These findings are important because resistance to infection is a very overlooked consequence after a virus outbreak, mainly because identifying resistant individuals is very difficult – because they don't get sick after being exposed to the virus, they don't necessarily know they have been exposed to the virus
.
That's why such cohorts, albeit tragic in nature, are incredibly valuable — they provide a unique opportunity to study how healthy people respond
to viral infections.
”

The lab's work is now focused on using these biological findings to crack viral resistance genes
in HCV donors.
Their work on HCV drug resistance has helped spur international interest in drug resistance to other viral infections, including the SARS-CoV-2 virus
that causes COVID-19.

O'farrelly Labs has expanded its search
for virus-resistant individuals by joining COVID Human Genome Research and recruiting large numbers of members of the public who have been exposed to SARS-CoV-2 but have never been infected.

Jamie A.
Sugrue, Cé line Posseme, Ziyang Tan, Christian Pou, Bruno Charbit, Vincent Bondet, Nollaig M.
Bourke, Petter Brodin, Darragh Duffy, Cliona O’ Farrelly.
Enhanced TLR3 responsiveness in hepatitis C virus resistant women from the Irish anti-D cohort.
Cell Reports Medicine, 2022; 100804