HTLV-1 Enhances Epstein-Barr Virus (EBV) Infectivity and EBV Infection Attributes to an Aggressive Organ Involvement in Adult T-Cell Leukemia.

The frequent involvement of adult T-cell leukemia (ATL) cells in organs such as the skin and lymph nodes is observed in ATL. Epstein-Barr virus (EBV) infection has been observed in the clinical course of ATL, and ATL cells in all skin cases were strongly positive for EBV nuclear antigen (EBNA)-1 and latent membrane protein (LMP)-1 by immunohistochemical staining. Interestingly, ATL cells in all skin cases were positive for CD45R0 (UCHL1) and CD20 (L26), indicating that they have both T and B cells characterization. We suggested that HTLV-1 enhances the entry of EBV into endothelial cells, epithelial cells and EBV presents for an active role of HTLV-1 in the development of ATL. Here, we established two B-cell lines from peripheral blood of patients with ATL. EBV DNA, proviral DNA for HTLV-1 and Tax mRNA were detected in both B cell lines. On characterization of the cell lines, enhanced expression of intercellular adhesion molecule-1 or-3 (CD54, CD50), lymphocyte function-associated antigen-1 (CD11a/CD18) and Mac-1 (CD11b/CD18) was observed compared to an EBV-infected B cell line, Raji. Moreover, EBV oncogenes such as EBV-encoded small RNA (EBER)-1, EBNA-1,-2 and LMP-2A were also detected. To investigate the role of the interaction of these viruses, we transfected EBV and/or HTLV-1 into a healthy donor’s lymphocytes, Raji cells and a HTLV-1 negative T-cell line, Jurkat. Enhanced expression of adhesion molecules was observed in double transfectants (EBV and HTLV-1). Furthermore, we detected high production levels of interleukin-4 (IL-4) in those B-cell lines and transfectants. These results indicated co-expression of HTLV-1 and EBV may induce aggressive organ involvement by enhanced expression of adhesion molecules via IL-4 signaling. Furthermore, HTLV-1 could greatly enhance EBV infectivity and attribute to increased replication of EBV. EBV also could be a necessary cofactor for ATL development in immunodeficiency states. ATL patients who have been coinfected with EBV and HTLV-1 have a high risk of worse progress of disease. ATL patients have a poor treatment outcome, even with strong chemotherapy, especially who have severe skin involvements have a resistance for chemotherapy. Viewed from a different angle, our observations suggest that EBV infection may be used as one of bad prognostic factors and an identification of bad-risk patients who need to benefit from early high dose chemotherapy. Collectively, a reactivation of EBV infection and EBV oncogenes can provide an acceleration of organ involvement in ATL.These results can explain why EBV-associated ATL is more frequent and clinically more aggressive.