IMMUNITY AGAINST EBV: GENERAL OVERVIEW
INBORN ERRORS OF IMMUNITY TO EBV
BIOLOGY OF EBV AND ITS RELATIONSHIP TO HUMAN CANCERS
Epstein-Barr Virus (EBV) EBNA and LMP proteins and the viral miRNAs cause growth of infected human B lymphocytes, giving cells which resemble some lymphomas observed in immunodeficient patients. Infection of human T lymphocytes may also occur with some strains of EBV. EBV associated cancers in immunocompetent patients involve altered expression or mutation of cell genes in combination with some EBV gene functions. Immune evasion mechanisms play important roles in the normal virus life cycle and in cancers of immunocompetent patients.
The EBV genome can express over 100 gene products. After sequencing the EBV from many normal and cancer cell infections worldwide, we analysed a multiple sequence alignment of 241 EBV genomes. The largest variation is between type 1 and type 2 EBV, mediated by sequence difference in the EBNA2 and EBNA3 regions of the genome. Although type 1 EBV is much more effective at transforming B cells than type 2 EBV, both types can be involved in cancers. The greater ability of type 1 EBV to transform human B lymphocytes is partly due to a weaker interaction of type 1 EBNA2 with the cell BS69 protein. BS69 can obstruct the transcription factor activity of EBNA2. Searching for virus sequence variation that is linked to cancer development has identified a single nucleotide variation which creates an additional NFAT site in the promoter for the EBV BZLF1 virus replication activator. Strains with this variation activate virus replication more strongly and are enriched in EBV associated cancers.
EBV POSITIVE SMOOTH MUSCLE TUMORS AS MANIFESTATION OF INBORN ERRORS OF IMMUNITY
EBV positive smooth muscle tumors are a rare oncological entity that can develop in secondary immunodeficiency such as human immunodeficiency virus-infection or solid organ transplantation. In addition, in rare pediatric cases EBV positive smooth muscle tumors can develop in the context of primary immunodeficiency such as CARMIL2 deficiency. In secondary immunodeficiency and when the underlying condition can not be cured, the treatment of EBV positive smooth muscle tumors is based on surgery in combination with antiretroviral and reduced or altered immunosuppressive pharmacotherapy, respectively. However, when cellular immunity cannot be reestablished or EBV positive smooth muscle tumors cannot completely be resected, long-term survival is poor. Importantly, allogeneic hematopoietic blood stem cell transplantation resulted in cure of immunodeficiency and EBV positive smooth muscle tumors in a GATA-2 deficient patient and is ongoing in a CARMIL2 deficient patient. Thus, in the absence of secondary immunodeficiency patients presenting with EBV positive smooth muscle tumors should be thoroughly evaluated for primary immunodeficiency disorders and patients with known primary immunodeficiency presenting with smooth muscle tumors should be evaluated for an underlying ectopic EBV infection. Allogeneic hematopoietic stem cell transplantation should be taken into consideration in these cases.