Epstein-Barr virus and the B cell: that's all it takes.

Recent experiments demonstrate that a much broader range of B cells harbor Epstein-Barr virus (EBV) in vivo than was previously expected from in vitro studies. In this review it is argued that EBV persists in vivo by integrating its biology with that of the normal B cells within which it resides, and that the B cell provides all the environments necessary for EBV to maintain its life cycle.

Identification of the site of Epstein-Barr virus persistence in vivo as a resting B cell.

Epstein-Barr (EBV) is a powerful immortalizing virus for human B lymphocytes in vitro and is associated with several human neoplasias in vivo. Previously, we have shown that the majority of EBV-infected cells in the peripheral blood of healthy, persistently infected individuals do not express the activated phenotype, e.g., high levels of cell surface CD23 and CD80 (B7), characteristically expressed on in vitro-immortalized cells. Here, we show that > or = 90% of the CD23-, virus-infected cells in the peripheral blood are in G0 and therefore resting. The remaining cells may be G1 arrested, but we were unable to detect a significant number of cells traversing the S-G2-M stages of the cell cycle. The mRNA for LMP2A, but not EBNA1 originating from Qp, was readily detected in this population, and these cells appear competent in the processing and presentation of antigen by class I major histocompatibility complex. We propose that these resting B cells are the site of long-term latent persistence for EBV. We further propose that the persistence of the virus in a resting B7- B cell provides an important mechanism to escape immunosurveillance. The demonstration that EBV can persist latently in a resting B cell means that the immortalizing functions of EBV can be down regulated in a normal B cell. This conclusion has important implications for understanding and controlling EBV-associated neoplasia.

Is EBV persistence in vivo a model for B cell homeostasis?

We have measured the absolute numbers of EBV-infected B cells in the peripheral blood of healthy persistently infected individuals. Single measurements on a panel of 15 healthy individuals demonstrate that the frequency varies over a wide range from 1-50 per 10(6) B cells. Repeat measurements over 1-3.5 years on several individuals whose frequencies varied over a 10-fold range showed that the variation does not represent the fluctuation in the frequency that can occur within an individual; rather, the frequencies are specific to the individual. The frequency within an individual measured over time is stable and contributes less than 10% to the variance seen in the whole population. These measurements suggest that the level of EBV-infected B cells is tightly regulated and we propose that the same homeostatic mechanisms that regulate the levels of normal B cells also regulate B cells latently infected with EBV.

A novel form of Epstein-Barr virus latency in normal B cells in vivo.

We have developed a PCR assay that can detect a single Epstein-Barr virus (EBV) genome in the presence of 10(6) uninfected cells. Using this assay, we demonstrate that EBV persists, in the peripheral blood of all seropositive individuals tested, in CD19+, CD23-, and CD80 (B7)- B cells. We further show that the virus in these cells is latent, but readily reactivated to produce infectious immortalizing virus; therefore, these cells represent a true site of latent persistence. EBV was not significantly detected in monocytes or T cells. The frequency of infected cells in nine healthy donors varied from 23 to 625 per 10(7) B cells, but was relatively stable for each individual over the course of 2 years. We conclude that the EBV-infected cells in vivo are B cells with a nonactivated phenotype. This represents a novel form of latency in normal B cells.