Development of progressive multifocal leukoencephalopathy during natalizumab treatment. This figure summarizes the three hypotheses on how natalizumab may lead to PML. (a) Natalizumab may prevent the entry of JCV-specific cytotoxic T cells into the brain, necessary for the control of latent JCV within infected oligodendrocytes. (b) Natalizumab inhibits the VLA-4-dependent homing and retentions of lymphocytes in bone marrow (sites of JCV latency), thus leading to an increase of JCV-infected peripheral leukocytes. Finally, another possible factor is the natalizumab-induced expression of Spi-B, a transcription factor that has been shown to increase JCV transcription.