Co-Infection of the Epstein-Barr Virus and the Kaposi Sarcoma-Associated Herpesvirus

Abstract

The two human tumor viruses, Epstein-Barr virus (EBV) and Kaposi sarcoma-associated herpesvirus (KSHV), have been mostly studied in isolation. Recent studies suggest that co-infection with both viruses as observed in one of their associated malignancies, namely primary effusion lymphoma (PEL), might also be required for KSHV persistence. In this review, we discuss how EBV and KSHV might support each other for persistence and lymphomagenesis. Moreover, we summarize what is known about their innate and adaptive immune control which both seem to be required to ensure asymptomatic persistent co-infection with these two human tumor viruses. A better understanding of this immune control might allow us to prepare for vaccination against EBV and KSHV in the future.

Keywords: B cell lymphomas; Kaposi sarcoma; T cells; cytotoxic lymphocytes; humanized mice; latent and lytic infection; natural killer cells.

Figure 1

Expression of lytic EBV and KSHV genes can condition the tumor microenvironment. Primary effusion lymphoma (PEL) is associated with KSHV, however 90% of tumors also carry EBV. EBV and KSHV most likely contribute to the tumor environment simultaneously through their lytic gene expression. Lytic KSHV expression contributes through expression of K1, which promotes expression of VEGF and angiogenesis. viral G-protein coupled receptor expression promotes proliferation. Expression of the viral cytokine vIL6 promotes production of IL6 and IL10 and increases PEL proliferation. EBV lytic gene expression contributes through CCL5 production that attracts monocytes, which as tumor associated macrophages (TAM) have immune suppressive functions. Expression of viral IL10 can suppress CD8⁺ T cell responses.

Figure 2

Balance between host immune responses and viral immune modulation mechanisms allow persistence of KSHV. TLR, RLR, NLR and intracellular DNA-sensor cGAS are the four PRRs reported to sense KSHV infection (blue) and to induce NF-κB-mediated inflammatory cytokine production, type I IFN response and inflammasome activation (white). KSHV immune evasions (red) counteract PRR-induced signaling pathways via different means, e.g., via reducing the expression of signaling proteins (miR-K9/K5, RTA, kb-ZIP), via suppression of cellular proteins by viral homologues (vIRF1-4, ORF63), via targeting signaling proteins for proteasomal degradation (RTA) or via inhibition of nuclear translocation of signaling proteins (ORF45). Cellular innate immune response is modulated by reducing cytotoxicity of NK cells via driving differentiation into a late phenotype characterized by CD39 expression and loss of NKG2D, via downregulation of activating NK cell receptor ligands and via inhibiting NK cell migration by viral chemokine secretion. IFN-γ derived from NK cells, CD8⁺ or Th1 CD4⁺ T cells might protect from KSHV-associated malignancies, although T cell correlates conferring protection from KSHV-associated malignancies are not fully understood.