Epstein-Barr Virus

Cancer-Causing Viruses Hijack Human Protein to Evade Immune Response

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Viruses have evolved with humans for millions of years, so it’s no surprise they’ve evolved tricks to evade our natural, or innate, immune responses. Unfortunately, it’s often unclear what these tricks are. But now, thanks to researchers at the University of North Carolina (UNC) School of Medicine, one of these tricks has been revealed. It is particular to gammaherpesviruses, which include Kaposi sarcoma-associated herpesvirus (KSHV) and Epstein-Barr virus (EBV).

These viruses, which are DNA viruses, have been linked to several cancers and establish lifelong latency in the human population. According to the UNC researchers, these viruses use a human protein called barrier-to-autointegration factor 1, or BAF, to evade our innate immune response, allowing the viruses to spread and cause disease.

The researchers suggest that BAF and related proteins could prove to be valuable therapeutic targets. Indeed, if these targets can be engaged, it may be possible to prevent virus-instigated cancers such as Kaposi sarcoma, non-Hodgkin lymphoma, Hodgkin lymphoma, multicentric Castleman disease, nasopharyngeal carcinoma, and gastric cancer.

Details about the new research appeared in Nature Communications, in an article titled, “Barrier-to-autointegration factor 1 promotes gammaherpesvirus reactivation from latency.”

“We report that barrier-to-autointegration factor 1 (BAF)-mediated suppression of the cGAS-STING signaling pathway is necessary for reactivation of KSHV and EBV,” the article’s authors wrote. “We demonstrate a role for BAF in destabilizing cGAS expression and show that inhibiting BAF expression in latently infected, reactivating, or uninfected cells leads to increased type I interferon-mediated antiviral responses and decreased viral replication. Furthermore, BAF overexpression resulted in decreased cGAS expression at the protein level.”

The research was led by Blossom Damania, PhD, the Boshamer distinguished professor of microbiology and immunology and member of the Lineberger Comprehensive Cancer Center. She stated, “Viruses are in a constant battle with the cellular immune system, which includes the protein cyclic GMP-AMP synthase, or cGAS, which binds to viral DNA and sounds the alarm to trigger immune responses and fight the viral invaders. We’ve discovered that KSHV and EBV use a different host cell protein, BAF, to prevent cGAS from sounding the alarm.”

In the case of KSHV and EBV, the expression of BAF is increased upon infection, suggesting that these viruses take advantage of this host protein to blunt the immune response to infection. In a series of experiments, Damania’s laboratory found that BAF contributes to the degradation of the cGAS DNA sensor. With less cGAS protein available in the infected cell to detect DNA, the cells mount weaker immune responses, which allows these two viruses to replicate and spread more efficiently.

“BAF enables EBV and KSHV to reactivate from latency, replicate, and make more of themselves,” said first author Grant Broussard, a graduate student in the genetics and molecular biology curriculum at UNC Lineberger. “Our study highlights the prominent role that DNA detection pathways like the cGAS pathway play in controlling viral infection.”

He stressed that disrupting BAF activity with targeted therapies could reduce its immunosuppressive effects, thus restricting replication of these viruses to prevent the spread of disease.

Damania, who is a Leukemia and Lymphoma Society scholar and a Burroughs Wellcome Fund investigator in infectious diseases, added, “Preventing lytic replication will prevent transmission of these viruses and also reduce the global cancer burden associated with these two viruses.”

Epstein-Barr Virus Tracking After Liver Transplant May Cut Rare Complication

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Observational study provides suggestive evidence

A photo of a blue rubber gloved hand holding a test tube labeled: EPSTEIN-BARR VIRUS (EBV) TEST

Monitoring Epstein-Barr virus (EBV) levels after liver transplantation to avoid over-immunosuppression showed a signal for less post-transplant lymphoproliferative disease (PTLD) over the long term in an observational study.

Standardized incidence of PTLD was consistently numerically lower over time at a hospital that used EBV monitoring for liver transplant patients compared with one that didn’t, reported Bart van Hoek, MD, PhD, of Leiden University Medical Center in the Netherlands, and colleagues in the Annals of Internal Medicineopens in a new tab or window.

Accounting for decreasing PTLD rates over time by looking at the difference between hospitals for the contemporary period versus a historical period at the same hospital, the estimates ranged from 28.7 to 70.6 fewer incident PTLD cases with monitoring per 1,000 patients over 5 to 15 years of follow-up.

However, none of the differences in differences were statistically significant.

The monitoring strategy hospital had more patients require rejection treatment, especially in the first 3 months after transplantation, compared with the control hospital, “which could be associated with a reduction in immunosuppression,” van Hoek and team noted. However, “all of these rejections were easily treatable and did not lead to graft loss.”

By contrast, PTLD is associated with morbidity and mortality, and is thus of “utmost importance” to avoid, they argued. While EBV infection or reactivation is asymptomatic in most liver transplant patients, approximately 70% of PTLD cases that do occur are related to this highly prevalent virus.

“The current data contradict the conclusion from [a prior retrospective] studyopens in a new tab or window that EBV viremia is benign, and on the basis of the current data, we consider detectable EBV VL [viral load] as a sign of over-immunosuppression, which can lead to B-lymphocyte proliferation and PTLD,” van Hoek’s group wrote.

Despite the limitations of the retrospective observational study, “we strongly believe that the reported results merit serious consideration of the EBV VL monitoring policy in an attempt to reduce the incidence of PTLD after LT [liver transplant] in adults,” they noted. “At least such a strategy seems safe.”

van Hoek and colleagues examined health records for adult recipients of a first liver transplant at Leiden University Medical Center after it started routine EBV DNA monitoring on liver transplant patients in September 2003. The program involved weekly monitoring in the first month after transplantation, biweekly monitoring in the second month, and then monthly or when patients came for additional visits for the rest of the first year. Thereafter, the viral load was measured at least yearly.

The 302 patients treated under the EBV viral load monitoring strategy through January 2017 were compared with 116 historical controls with corresponding transplants from September 1992 until the start of monitoring.

Among the 12% of monitored patients who had two or more positive viral load measurements within 2 months in the first year after transplant, 89% had their immunosuppression regimen reduced as required by the protocol. Of the 21% of the monitored patients with a single positive viral load result followed by an undetectable level on the repeat test, 44% had their immunosuppression reduced based on physician judgment. Altogether, 33% had at least one detectable EBV viral load measurement in the first year, and 60% of this group had their immunosuppression reduced.

After the first year, 25% of patients had at least one positive EBV viral load result, with 46% having their immunosuppressive medication reduced.

Another contemporary control group at a second university medical center who didn’t undergo EBV monitoring included 579 liver transplant patients from September 2003 through January 2017. A fourth group, of historical controls at that center, included 284 patients from 1986 through January 2003.

The historical control group at both centers had numerically but not significantly more PTLD events compared with the contemporary era (crude incidence 25.5 vs 13.3 per 1,000 patients at the control center and 40.4 vs 4.2 per 1,000 at the monitoring center), which the researchers suggested was “likely to be related to less immunosuppression in contemporary versus historical patients, similar to renal transplant.”

Their main results utilized an inverse probability of treatment-weighted number of patients for PTLD, because distributions showed “many influential outliers.” Replacing scores above the 95th percentile with the 95th percentile and those below the fifth percentile with the fifth percentile improved but did not achieve complete balance in initial characteristics.

The cohort had an average age of 46.2 to 53.2 across groups, and 53.2% to 71.9% were men. EBV immunoglobulin G positivity was 96.0% to 99.1%.

Other limitations to the study included the use of persistently detectable EBV viral levels as the threshold for treatment decisions, although the level above which action is required has not been well established and even the same plasma assay analyzed in a different laboratory could generate a different detection limit cutoff, as the researchers noted.

“An EBV VL monitoring strategy with immunosuppression reduction may reduce the incidence of PTLD in other adult patients with long-term immunosuppression and may contribute to tumor surveillance and prevention of other infections; however, future studies should confirm this,” they concluded.