Figure 6.

Hypothetical mechanism of BLV replication. Normal B cell activation and proliferation depend on a variety of immune stimuli, involving the BCR (and possibly CD5, section 3), CD40 ligand expressed by T cells, various cytokines or even autoantigens (see section 5). We hypothesize that BLV replication is initiated by these classical regulatory mechanisms because viral expression can be augmented by molecules that mimic B cell activation by immune cells. Tax expression precedes that of structural and enzymatic proteins and promotes entry into the cell cycle, providing a selective proliferative advantage of the infected cells (see section 4, The Tax transactivator). Uneven distribution of the viral proteins upon mitosis would generate two types of infected cells containing or not BLV antigens (see section 4, The envelope gene). Other processes might account for silencing of viral expression in one daugther cell such as a specific inhibition by a viral factor such as HTLV p30 or HBZ (still to be discovered for BLV). We think that BLV expression is ongoing continuously in vivo because viral transcripts are detected in whole blood immediately upon incubation at 37°C in the absence of any exogenous factors (see section 5, Low levels of viral expression are detected in vivo). Virus-positive cells would be destroyed by the immune response (see section 5, Host humoral and cytotoxic immune responses) or would undergo apoptosis via intrinsic or extrinsic pathways (section 6: Is BLV inhibiting apoptosis?). These cells would thus permanently stimulate the host's immune response. Cells in which viral expression has been shut off or lacking viral antigens after mitosis would enter a resting stage in the absence of Tax and/or immune stimulation. These cells surviving destruction by the immune response can be isolated and observed ex vivo.