Expression of CTLA-4 and CD86 Antigens and Epstein-Barr Virus Reactivation in Chronic Lymphocytic Leukemia—Any Link with Known Prognostic Factors?

SIMPLE SUMMARY: Chronic lymphocytic leukemia (CLL) accounts for one-third of all leukemias. The Epstein-Barr virus (EBV) has the ability to transform B-cells into cancer cells. A history of EBV infection increases the chances of acquiring CLL and it worsens the prognosis in CLL. We tried to assess whether EBV affects the course of CLL by deregulating the CTLA-4/CD86 pathway. The expression of CTLA-4 and CD86 on immune cells in patients with CLL has been evaluated and linked to indicators of EBV infection and clinical outcomes. Our studies have shown that anergy, which is expressed by inhibition through the interaction of CTLA-4 and CD86, is an important mechanism leading to the inhibition of the antitumor response and CLL progression. ABSTRACT: Infection with Epstein-Barr virus (EBV) worsens the prognosis in chronic lymphocytic leukemia (CLL), but the underlying mechanisms are not yet established. We intended to assess whether EBV affects the course of CLL by the deregulation of the CTLA-4/CD86 signaling pathway. We used polymerase chain reaction to measure the load of EBV DNA in the blood of 110 newly diagnosed patients with CLL. The expression of CTLA-4 and CD86 antigen on lymphocytes was assessed with flow cytometry. Additionally, CTLA-4 and CD86 serum concentrations were measured through enzyme-linked immunosorbent assays. Fifty-four percent of the patients had detectable EBV DNA [EBV(+)]. In EBV(+) patients the CTLA-4 and CD86 serum concentrations and their expressions on investigated cell populations were significantly higher than in EBV(−) patients. EBV load correlated positively with unfavorable prognostic markers of CLL and the expression of CTLA-4 on CD3+ lymphocytes (r = 0.5339; p = 0.027) and CD86 on CD19+ cells (r = 0.6950; p < 0.001). During a median follow-up period of 32 months EBV(+) patients were more likely to require treatment or have lymphocyte doubling (p < 0.001). Among EBV(+) but not EBV(−) patients, increased expressions of CTLA-4 lymphocytes were associated with elevated risks of progression. We propose that EBV coinfection may worsen prognosis in CLL patients, partly due to EBV-induced up-regulation of CTLA-4 expression.