Abstract
Epstein-Barr virus (EBV) and Kaposi sarcoma-associated herpesvirus (KSHV) comprise the oncogenic human γ-herpesvirus family and are responsible for 2-3% of all tumours in man. With their prominent growth-transforming abilities and high prevalence in the human population, these pathogens have probably shaped the human immune system throughout evolution for near perfect immune control of the respective chronic infections in the vast majority of healthy pathogen carriers. The exclusive tropism of EBV and KSHV for humans has, however, made it difficult in the past to study their infection, tumourigenesis and immune control in vivo. Mice with reconstituted human immune system components (humanized mice) support replication of both viruses with both persisting latent and productive lytic infection. Moreover, B-cell lymphomas can be induced by EBV alone and KSHV co-infection with gene expression hallmarks of human malignancies that are associated with both viruses. Furthermore, cell-mediated immune control by primarily cytotoxic lymphocytes is induced upon infection and can be probed for its functional characteristics as well as putative requirements for its priming. Insights that have been gained from this model and remaining questions will be discussed in this review. This article is part of the theme issue 'Silent cancer agents: multi-disciplinary modelling of human DNA oncoviruses'.
Highlights
The two human g-herpesviruses Epstein –Barr virus (EBV or HHV4) and Kaposi sarcoma-associated herpesvirus (KSHV or HHV8) are among the seven viruses that the World Health Organization has classified as class I carcinogens (besides human papilloma virus (HPV), Merkel cell polyomavirus (MCPyV), hepatitis B and C viruses and human T-cell lymphotropic virus 1 (HTLV-1)) [1,2,3]
Cognate antigen recognition by the B-cell receptor and ensuing plasma cell differentiation are thought to trigger lytic EBV replication [15]. These premalignant states of oncogenic EBV gene expression programmes are seemingly kept in check by immune control, which will be discussed in further detail below
It has been reported that the inhibition of lytic herpesvirus replication was able to prevent KS in patients and has been used to treat individual primary effusion lymphoma (PEL) cases [19,67 –70]. These studies suggest that humanized mice develop B-cell lymphomas after EBV single or co-infection with KSHV with similarities to the respective human hematologic malignancies, and that lytic EBV replication contributes to tumour formation
Summary
The two human g-herpesviruses Epstein –Barr virus (EBV or HHV4) and Kaposi sarcoma-associated herpesvirus (KSHV or HHV8) are among the seven viruses that the World Health Organization has classified as class I carcinogens (besides human papilloma virus (HPV), Merkel cell polyomavirus (MCPyV), hepatitis B and C viruses and human T-cell lymphotropic virus 1 (HTLV-1)) [1,2,3]. Infection with EBNA3A and 3C-deficient viruses was restricted to secondary lymphoid tissues and persisted for at least three months At this time point, primarily non-translated EBV RNA without latent protein expression could be detected in EBV-infected B cells. It has been reported that the inhibition of lytic herpesvirus replication was able to prevent KS in patients and has been used to treat individual PEL cases [19,67 –70] These studies suggest that humanized mice develop B-cell lymphomas after EBV single or co-infection with KSHV with similarities to the respective human hematologic malignancies, and that lytic EBV replication contributes to tumour formation. The tumour microenvironment that is most likely stimulated by lytic reactivation significantly contributes to the robustness of EBV-associated malignancy development Along these lines, it was reported that LMP1-deficient EBV can cause lymphomas, but requires CD4þ T-cell help for lymphomagenesis [47]. These findings suggest that humanized mice can model B-cell lymphomas with transcriptional similarities to human tumours after EBV and KSHV infection, and, that contributions of the tumour microenvironment to lymphomagenesis can be studied
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