Researchers led by Blossom Damania, PhD, reported that Kaposi sarcoma-associated herpesvirus, a virus linked to three human cancers, uses a protein produced by its human host to come out of hiding and reactivate.
A virus linked to three cancers uses a protein produced by its human host to come out of hiding and reactivate, according to University of North Carolina Lineberger Comprehensive Cancer Center researchers.
Researchers reported in a new study that Kaposi sarcoma-associated herpesvirus, a virus linked to three human cancers, uses the host cellular protein ADAR1 to reactivate itself from a dormant phase and replicate. The findings, published in Cell Reports, could point to a potential therapeutic target to prevent Kaposi sarcoma-associated herpesvirus from growing and spreading.
“We have found a host cell protein that actually facilitates the production of a human oncogenic virus,” said UNC Lineberger’s Blossom Damania, PhD, vice dean for research in the UNC School of Medicine and the Boshamer Distinguished Professor in the Department of Microbiology and Immunology.
Kaposi sarcoma-associated herpesvirus can cause three cancers: Kaposi sarcoma, primary effusion lymphoma and multicentric Castleman’s disease. People are more likely to develop these cancers if they are infected with the virus and their immune system has been weakened, such as by infection with human immunodeficiency virus (HIV) or if they are immunosuppressed for other reasons.
Researchers knew that the virus has mechanisms to block the immune system, and now their evidence points to ADAR1 as a co-conspirator in helping the virus avoid detection.
Normally, ADAR1 is used in human cells and prevents the immune system from being activated in response to naturally-occurring double-stranded RNA in human cells. Researchers said constant activation of the immune system by naturally occurring double-stranded RNA can cause chronic inflammation, which can be problematic.
“ADAR1 is responsible for editing double-stranded RNAs to prevent the host from detecting self RNAs, and such ADAR1-mediated editing is important for counteracting inflammation,” Damania said.
However, in infected cells, researchers reported the virus uses ADAR1 to prevent detection of its own double-stranded RNA molecules by the host’s front-line immune system.
When they depleted ADAR1 protein in human cells infected with Kaposi sarcoma-associated herpesvirus, they hindered the virus from copying its DNA and from replicating as the virus was emerging from dormancy. They found the decreased viral replication was due to an increase of the immune signal interferon.
“The cellular protein ADAR1 enables Kaposi sarcoma-associated herpesvirus to replicate and make more of itself,” said Huirong Zhang, PhD, the study’s co-first author and a postdoctoral research associate at UNC Lineberger.
In future studies, Guoxin Ni, PhD, a postdoctoral research associate at UNC Lineberger and the other co-first author of the paper, said the researchers plan to study exactly how ADAR1 helps the virus replicate in the host cell. They also believe that they could potentially use the findings to stop the reactivation and replication of the Kaposi sarcoma-associated herpesvirus.
“Preventing lytic reactivation and replication of the virus will prevent transmission and spread of the oncogenic virus,” Damania said. “This would also reduce the cancer burden if we could reduce the virus’ spread.”
The study was supported by the National Institutes of Health. Damania is a Leukemia and Lymphoma Society Scholar and a Burroughs Wellcome Fund Investigator in Infectious Diseases.