Increased Frequency of the Chemokine Receptor CCR2 on Circulating CD19+CD5+ Lymphocytes in Therapy-Naïve CLL Patients With the Detectable EBV DNA and High-Avidity Antibodies Against the EBV Capsid Antigen.

High EBV load in peripheral blood (PB) of untreated patients with chronic lymphocytic leukemia (CLL) has been associated with shorter overall survival. We demonstrated previously that EBV infection of B cells upregulates CCR1 and CCR2. For 54 therapy-naïve CLL patients of the present study, we analyzed expression of CCR1, CCR2, and CD38 on circulating CD19+CD5+ lymphocytes, determined the EBV load (EBV DNA copy number) and the EBV transcripts (BZLF1, LMP1, LMP2A, and EBNA2) in PB mononuclear cells (PBMCs), and measured levels and avidity of IgG antibodies against the EBV capsid antigen (anti-EBV-CA-IgG). The BZLF1 transcript was determined in one patient; both LMP1 and EBNA2 transcripts were detected in two patients only, and, in these patients, the frequency of CD19+CD5+ lymphocytes that presented CCR1 or CCR2 was elevated by 2.5-, 4.3-, and 2.9-fold and by 2.1-, 1.2-, and 2.9-fold, respectively, relative to the median values in the EBV-positive group (> 5 EBV DNA copies in 105 PBMCs; n = 21). The levels and avidity of anti-EBV-CA-IgG were significantly higher in EBV-positive patients compared with the EBV-undetectable group (p = 0.007 and p = 0.018, respectively). Noteworthy, the high avidity of anti-EBV-CA-IgG, with the relative avidity index (RAI) range 61.0-94.6, was associated in EBV-positive patients with the increased 2.3-fold frequency of CCR2 on CD19+CD5+ lymphocytes, compared to patients with the highest avidity (RAI > 95.0; p = 0.006). In patients with the highest anti-EBV-CA-IgG avidity (RAI > 95.0; n = 13), indicative of the high rate of antigen presentation and a recent lytic viral reactivation, the frequency of the CCR2-presenting CD19+CD5+ PB lymphocytes was 1.7-fold lower than the median value of all high-avidity patients (n = 31; p = 0.032). We hypothesize that CCR2 directs the migration of leukemic lymphocytes from circulation into ligand-rich lymphoid organs, thereby underlying EBV's contribution to CLL progression.