Persistent KSHV Infection Increases EBV-Associated Tumor Formation In Vivo via Enhanced EBV Lytic Gene Expression

Abstract

The human tumor viruses Epstein-Barr virus (EBV) and Kaposi sarcoma-associated herpesvirus (KSHV) establish persistent infections in B cells. KSHV is linked to primary effusion lymphoma (PEL), and 90% of PELs also contain EBV. Studies on persistent KSHV infection in vivo and the role of EBV co-infection in PEL development have been hampered by the absence of small animal models. We developed mice reconstituted with human immune system components as a model for KSHV infection and find that EBV/KSHV dual infection enhanced KSHV persistence and tumorigenesis. Dual-infected cells displayed a plasma cell-like gene expression pattern similar to PELs. KSHV persisted in EBV-transformed B cells and was associated with lytic EBV gene expression, resulting in increased tumor formation. Evidence of elevated lytic EBV replication was also found in EBV/KSHV dually infected lymphoproliferative disorders in humans. Our data suggest that KSHV augments EBV-associated tumorigenesis via stimulation of lytic EBV replication.

Identification of Host Biomarkers of EBV Latency IIb and Latency III

“…This was hypothesized to be due to the increased immunogenicity of latency III cells (26). Similarly, a recent study using a mouse model of EBV/KSHV co-infection, latency IIb cells were detected at a high frequency (16). The pathophysiological relevance of latency IIb therefore supports our study to define latency-distinguishing host markers.…”

“…Staining patient biopsies has demonstrated heterogeneity at the single cell level where many cells may be EBNA2-positive but negative for LMP1 (14, 15). These cells are often quite common as recent studies in a mouse model of EBV and Kaposi Sarcoma Herpes Virus (KSHV) co-infection also identified a high frequency of EBNA2+/LMP1-cells (16). Due to the wide distribution of LMP1 expression within a latency III LCL population, this technique does not allow for distinguishing LMP1 low latency III LCLs from LMP1 low latency IIb cells.…”

B Cell Receptor Activation and Chemical Induction Trigger Caspase-Mediated Cleavage of PIAS1 to Facilitate Epstein-Barr Virus Reactivation

“…We also found that PIAS1, but not PIAS2/3/4 gene level is significantly lower in EBV and KSHV-dually positive cell lines derived from infected huNSG mice, which support higher EBV lytic gene expression, than that in EBV-only cell lines derived from huNSG mice, which have lower EBV lytic gene expression (Figure S1M) (McHugh et al, 2017). …”

Mutual detection of Kaposi's sarcoma‐associated herpesvirus and Epstein–Barr virus in blood and saliva of Cameroonians with and without Kaposi's sarcoma

“…In addition, we cannot exclude that there might be a direct or indirect interaction between the two viruses, in this case, of cooperative type. Data from in vitro 41,42 and humanised animal models 43 studies suggest that such interactions, both cooperative and competitive, do exist. We previously observed in HIVuninfected Ugandan mothers and children, that KSHV and EBV salivary loads were inversely correlated, particularly in KSHV shedders, 40 suggesting a direct or indirect negative interaction.…”