Black Plague Left Clues for Fighting Hepatitis C, HIV

The black plague epidemic of the 14^th century left genetic clues that could help treat patients with both HIV and hepatitis C using an anti-retroviral drug therapy, a recent study suggests.

Researchers from the University of Cincinnati will study nearly 3000 blood samples from patients — primarily with hemophilia – who were exposed to HIV during the early 1980s and late 1990s. They are looking to see if the inherited genetic variant that currently protects against HIV could help prevent injury from hepatitis C and other liver diseases.

The study will focus on the protein CCR5 for ways to inhibit it. Two medications (Cenicriviroc and Maraviroc) that have been developed to block the CCR5 receptor and will be used in the study to learn the effect they have on clinical populations.

“It turns out that HIV and its evolution high-jacked that receptor and uses CCR5 as its primary way of binding to T-cells, entering them and killing them,” said researcher Kenneth Sherman, MD, PhD. “That's what causes AIDS. CCR5 is not just present on T-cells but also exists in the liver on the surface of hepatocytes and also in the liver on stellate cells. Stellate cells are the cells that produce scar tissue in the liver which can lead to the development of cirrhosis. The focus of this grant is to look at how inhibition of CCR5 might influence the development of liver injury and/or the development of scar or cirrhosis in the liver.

“An additional question to consider is, ‘How does interfering with CCR5 affect viruses like hepatitis C that might be co-infecting the liver?’” Sherman continued. “We know hepatitis C causes liver injury, but is that injury modulated in part through this receptor, which may not be a specific receptor for hepatitis C but is for HIV?”

Researchers hypothesize that an aberrant CCR5 protein created by the CCR5-delta 31 mutation could protect those who have been exposed to HIV but are without the rapid AIDS progression. This mutation came from the black plague epidemic.

“Research showed that Europeans and people of European descent who were selected genetically through their ancestors during the plague -- the black death of Europe -- and they have the CCR5-delta 32 mutation,” Sherman said. “This variant in the population also protected people from the plague. The disease was highly fatal in the 14th century. Many died, but some did not. Those who did not die from the plague were able to reproduce and pass forward the gene variant down through the generations. The gene was enriched in Europeans. If you have this gene, it's like taking a drug that blocks CCR5.”

By studying samples from patients with hemophilia, it opens the door for comparing fibrosis or liver scarring in those with the CCR5-delta 32 mutation versus those without it.

“We are using a very special group of patients, a long-term longitudinal cohort called the Multicenter Hemophilia Cohort Study,” Sherman said. “It was a study started in the early days of the HIV epidemic. It looked at outcomes of patients with hemophilia, many of whom developed HIV and hepatitis because of blood contamination. We have obtained samples from thousands of those patients and are studying differential outcomes in terms of liver disease to determine if CCR5-delta 32 mutation provided protection in those patients. If over the next few years, we can show that CCR5 blockade protects HIV-infected people from liver disease, then we may change the entire treatment paradigm of HIV and make this part of the routine treatment of many or most patients.”