How CypA Helps Viruses Avoid the Immune System

In a study published today in eLife, scientists discovered a trick that hepatitis C and other viruses use to evade the immune system. This finding allowed them to also identify an antiviral defense system that could be used to treat many viral infections.

Viruses have developed many strategies that allow them to avoid the immune system. One such strategy is to hijack the immune system’s own proteins—for example, cyclophilin A (CypA), which is targeted by HIV, hepatitis C, and the coronavirus SARS-CoV-2. Understanding how CypA is used by viruses could help scientists develop drugs that work against all of them, including SARS-CoV-2.

“Previously, clinical trials have shown that blocking CypA reduces the ability of the hepatitis C virus to replicate and boost the immune response,” explains first author Che Colpitts of Queen’s University, Kingston, Canada. “We set out to understand how CypA helps hepatitis C evade the immune system.”

The researchers used human liver cancer cells with and without a functioning immune system, which they infected with hepatitis C. Using a short hairpin RNA, they selectively silenced CypA in these cells—which stopped the virus from replicating only in the liver cells with a functioning innate immune system. The researchers also showed that drugs called cyclophilin inhibitors help block the virus from co-opting CypA and help prevent it from multiplying.

CypA is known to attach to an immune protein called protein kinase R (PKR), which affects its ability to detect viruses. So the team used CRISPR/Cas9 to cut out the gene for PKR in human liver cells with an otherwise working innate immune system. In cells without PKR, the cyclophilin inhibitors were less able to stop the virus from reproducing. This happened because PKR was not there to identify the virus and trigger antiviral defenses.

“These findings reveal a new antiviral defense mechanism that suppresses virus growth,” says senior author Greg Towers of the University College London. “This opens the door for the development of CypA-targeting antiviral drugs that can be used against many currently untreatable viruses.”