The tumor virus landscape of AIDS-related lymphomas

Abstract

• We evaluated a cohort of ARL samples for known and novel tumor viruses, revealing the oncogenic herpesvirus EBV as the sole detected infectious agent.• Heterogeneous viral gene expression suggests that variable host immunosurveillance of EBV latency may influence lymphomagenesis.Immunodeficiency dramatically increases susceptibility to cancer as a result of reduced immune surveillance and enhanced opportunities for virus-mediated oncogenesis. Although AIDS-related lymphomas (ARLs) are frequently associated with known oncogenic viruses, many cases contain no known transforming virus. To discover novel transforming viruses, we profiled a set of ARL samples using whole transcriptome sequencing. We determined that Epstein-Barr virus (EBV) was the only virus detected in the tumor samples of this cohort, suggesting that if unidentified pathogens exist in this disease, they are present in <10% of cases or undetectable by our methods. To evaluate the role of EBV in ARL pathogenesis, we analyzed viral gene expression and found highly heterogeneous patterns of viral transcription across samples. We also found significant heterogeneity of viral antigen expression across a large cohort, with many patient samples presenting with restricted type I viral latency, indicating that EBV latency proteins are under increased immunosurveillance in the post-combined antiretroviral therapies era. Furthermore, EBV infection of lymphoma cells in HIV-positive individuals was associated with a distinct host gene expression program. These findings provide insight into the joint host-virus regulatory network of primary ARL tumor samples and expand our understanding of virus-associated oncogenesis. Our findings may also have therapeutic implications, as treatment may be personalized to target specific viral and virus-associated host processes that are only present in a subset of patients. (Blood. 2015;125(20):e14-e22)

Comprehensive Transcriptome and Mutational Profiling of Endemic Burkitt Lymphoma Reveals EBV Type–Specific Differences

“…It has been argued that this observed expression pattern may primarily be due to various levels of lytic reactivation (54). Consistent with the previous reports (55), our results demonstrated similar heterogeneous viral gene expression in BL suggesting that tumor cells could be targeted by antiviral immunotherapies. Dysfunctional T cell immunity has been reported for children diagnosed with eBL who were defective for EBNA1 specific IFN-gamma T cell responses (56).…”

Immediate Antiretroviral Therapy Reduces Risk of Infection-Related Cancer During Early HIV Infection

“…The dominant EBV latency patterns observed in non-Hodgkin lymphoma tissue differ between pre- [33] and post-cART studies [34]. It was hypothesized that cART increases immune surveillance of proteins expressed by cells latently infected by EBV, resulting in a shift to a less oncogenic latency pattern [34].…”

Immunodeficiency-associated viral oncogenesis

“…In the HL, the malignant B-cell, expresses latency II program, called default program, and expresses the transforming LMP-1 protein as well as EBNA-1 and LMP-2 [reviewed in 19]. Very recently, Arvey et al [21], by using total RNA-seq technology (transcriptome sequencing) and the PathSeq analysis pipeline, found no virus other than EBV, in patients with AIDS-related lymphomas treated with ART. Furthermore, a highly heterogeneous pattern of viral transcription was found, with many cancer samples expressing the restricted type I viral latency, suggesting that EBV latency proteins are under high immunosurveillance [21].…”