Functional Epstein-Barr virus reservoir in plasma cells derived from infected peripheral blood memory B cells

Abstract

The Epstein-Barr virus (EBV) causes infectious mononucleosis, establishes latency in resting memory B lymphocytes, and is involved in oncogenesis through poorly understood mechanisms. The EBV lytic cycle is initiated during plasma cell differentiation by mRNAs transcripts encoded by BZLF1, which induce the synthesis of EBV proteins such as the immediate-early antigen ZEBRA and the late membrane antigen gp350. Therefore, we assessed the capacity of circulating EBV-infected B lymphocytes from healthy EBV-seropositive subjects to enter and complete the EBV lytic cycle. Purified B lymphocytes were polyclonally stimulated and BZLF1- or gp350-secreting cells (BZLF1-SCs or gp350-SCs) were enumerated by ELISpot assays. The number of BZLF1-SCs ranged from 50 to 480/107 lymphocytes (median, 80; 25th-75th percentiles, 70-150) and gp350-SCs from 10 to 40/107 lymphocytes (median, 17; 25th-75th percentiles, 10-20). gp350-SCs represented only 7.7% to 28.6% of BZLF1-SCs (median, 15%; 25th-75th percentiles, 10.5%-20%). This EBV functional reservoir was preferentially restricted to plasma cells derived from CD27(+) IgD(-) memory B lymphocytes. In 9 of 13 subjects, EBV DNA quantification in B-cell culture supernatants gave evidence of completion of EBV lytic cycle. These results demonstrate that EBV proteins can be secreted by EBV-infected B lymphocytes from healthy carriers, a majority generating an abortive EBV lytic cycle and a minority completing the cycle.

Downregulation of RUNX1 by RUNX3 Requires the RUNX3 VWRPY Sequence and Is Essential for Epstein-Barr Virus-Driven B-Cell Proliferation

“…BCMA has also been shown to be induced after B-cell activation, although its role at this stage is currently unknown (14). Current models for the EBV life cycle emphasize the role of the virus in aiding survival of infected B cells in the lymph nodes, where further differentiation can lead to the emergence of long-lived memory cells, in which the virus may persist indefinitely (1,32). EBV is associated with about 30% of cases of Hodgkin's lymphoma (HL) (29), and HL cells express BCMA, which generates survival signals upon APRIL stimulation (10).…”

B-cell polyclonal activation and Epstein-Barr viral abortive lytic cycle are two key features in acute infectious mononucleosis

“…Circulating EBV-infected B lymphocytes from healthy carriers when were polyclonally stimulated generate BZLF1-and MA-secreting cells (SCs) as measured by ELISpot assays, and only a minority of cells complete the cycle suggesting that the majority undergo an aborted lytic cycle. 10 …”

Pivotal role of HIV and EBV replication in the long-term persistence of monoclonal gammopathy in patients on antiretroviral therapy

“…1 T-cell replenishment (OR 5 18.6; 95% CI, 2.02-', P 5 .007, Duration of ART 9 (7-10) 9 (7)(8)(9)(10)(11)(12) .95…”

“…Patients' characteristics and treatments are presented in Table 1. EBV DNA in B cell, plasma EBV DNA, and ex vivo EBV-associated B cells were analyzed as previously described 10,11 and are detailed in the supplemental Data (available on the Blood website). This study was conducted in accordance with the Declaration of Helsinki.…”

“…9,10 The close relationship between EBV and lymphoproliferative disorders may include MG in HIV-infected patients. We hypothesized that the persistence of MG in HIV-infected individuals requires continuous B-cell stimulation fueled by both HIV and EBV replications.…”