Researchers make discovery of how cancer-causing virus evades early immune response

In a study published today in the journal Proceedings of the National Academy of Sciences, UNC Lineberger researchers report findings of how Kaposi’s sarcoma-associated herpesvirus, or KSHV, can inhibit a signaling pathway involved in triggering part of the early immune response to the virus.

Researchers make discovery of how cancer-causing virus evades early immune response click to enlarge Blossom Damania, PhD, is a UNC Lineberger member, co-director of UNC Lineberger’s Virology Program and of UNC Lineberger’s Global Oncology Program, and the Boshamer Distinguished Professor of Microbiology & Immunology.

UNC Lineberger Comprehensive Cancer Center researchers have uncovered a way that the cancer-causing Kaposi’s sarcoma-associated herpesvirus is able to get around part of the immune system’s first line of defense. The finding helps build our understanding of how the virus is able to integrate into a host and survive, and in some cases, cause cancer.

In a study published today in the journal Proceedings of the National Academy of Sciences, researchers report that several proteins made by Kaposi’s sarcoma-associated herpesvirus, or KSHV, can inhibit a signaling pathway called cGAS-STING. That pathway is important for triggering part of the immune response to the virus. The researchers hope the finding could help inform future research into potential therapeutic agents to protect the body from infection with this virus.

“Once you’re infected with the virus, you have it for life; there’s no cure. That’s why it’s important to understand the initial immune response to the viral infection,” said Blossom Damania, PhD, a UNC Lineberger member, co-director of UNC Lineberger’s Virology Program and of UNC Lineberger’s Global Oncology Program, and the study’s senior author. Damania is also the Boshamer Distinguished Professor of Microbiology & Immunology at the UNC School of Medicine, and an assistant dean of research in the school. “This virus has evolved with humans. We found that it has evolved a strategy to dampen the host response to it so it can better infect the host, and exist in the human population.”

The researchers were interested in studying KSHV and its interaction with the immune system because the virus is associated with three different cancers: Kaposi’s sarcoma, primary effusion lymphoma, and multicentric Castleman’s disease.

These cancers are seen worldwide. In the African country of Malawi where UNC-Chapel Hill is collaborating with the Malawi Ministry of Healthy to improve health through research, prevention, training and care, Kaposi’s sarcoma is the most common cancer type seen in men.

In a study using cells, the researchers found that a signaling pathway called cGAS-STING helped to control KSHV. The pathway responds to KSHV because it’s involved in monitoring and triggering responses to viruses that have DNA genomes, like KSHV.

The pathway is involved in activating the body’s innate immune response, which is the body’s initial response to an invading pathogen that's not specific to the type of invading microbe. Part of the early response is to activate molecules that can trigger other immune system cells against the pathogen.

The researchers studied activation of a protein called interferon, which acts as an alarm to trigger other immune cells to respond. They found that KSHV could block parts of the cGAS-STING signaling pathway, thereby lowering interferon levels. 

The researchers’ next step will be to try to understand how the viral proteins specifically interact with the immune system in order to prevent the proteins from blocking innate immune system activation.

“Understanding how the immune system responds to the viral infection is really important for developing future therapeutics that prevent the virus from infecting the human population,” Damania said.

The study was supported by the National Institutes of Health. Investigators working on the project were supported by the Leukemia & Lymphoma Society and the Burroughs Wellcome Fund Pathogenesis of Infectious Disease Award.

The study’s first author was Zhe Ma, a postdoctoral research associate at UNC Lineberger in the Damania lab. Additional co-authors included Sarah R. Jacobs, a postdoctoral research associate at UNC Lineberger; John A. West, a research associate at UNC Lineberger; Charles Stopford, a research specialist at UNC Lineberger: Zhigang Zhang, a research associate at UNC Lineberger; and Dirk P. Dittmer, PhD, co-director of the UNC Lineberger Global Oncology Program, a professor in the Department of Microbiology & Immunology, and a member of the UNC Center for AIDS. Additional collaborators were from the University of California at Berkeley and the University of Miami.