Numerous malignancies have been related to the viruses Epstein-Barr virus (EBV) and Kaposi sarcoma-associated herpesvirus (KSHV).
For the first time, UNC School of Medicine researchers have shown that these viruses elude our innate immune response by using a human protein called barrier-to-autointegration factor 1, or BAF, which enables the viruses to grow and cause illness.
These results, which were published in Nature Communications, imply that BAF and related proteins may be therapeutic targets to stop the spread of these viruses and the development of cancers like Kaposi sarcoma, non-Hodgkin lymphoma, Hodgkin lymphoma, multicentric Castleman disease, nasopharyngeal carcinoma, and gastric cancer.
According to Blossom Damania, Ph.D., the senior author and Boshamer Distinguished Professor of Microbiology and Immunology at UNC School of Medicine and member of the Lineberger Comprehensive Cancer Center, the viruses KSHV and EBV use the human protein BAF to evade the cellular immune system.
The immune system, including the protein cyclic GMP-AMP synthase (cGAS), is usually activated by binding to viral DNA, but KSHV and EBV prevent cGAS from sounding the alarm and trigger the immune response.
This discovery sheds new light on the constant battle between viruses and the cellular immune system.
Since viruses have coevolved with humans for millions of years, it is not surprising that they have developed strategies to escape our inborn immune systems. Finding out exactly how viruses do this is the first step to making vaccines and medicines that can stop them.
The increased production of BAF after KSHV and EBV infection suggests that these viruses exploit the host protein to stifle the immune response to infection.
In a series of tests, Damania’s lab found that BAF is part of what causes the cGAS DNA sensor to break down. The cells develop weaker immune responses because there is less cGAS protein accessible in the infected cell to recognize DNA, allowing these two viruses to multiply and spread more quickly.
Grant Broussard, the first author and a graduate student at UNC Lineberger’s Genetics and Molecular Biology Curriculum, said that BAF allows “EBV and KSHV to reactivate from latency, replicate, and make more of themselves.”
This work emphasizes the significant contribution of DNA-detecting pathways, such as the cGAS pathway, in viral infection control.
He said that stopping BAF from doing its job with targeted therapies could reduce its immune-suppressing effects. This would stop these viruses from spreading disease by stopping them from replicating.
“Preventing lytic replication,” according to Damania, “will prevent transmission of these viruses and also reduce the global cancer burden associated with these two viruses.”
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