In both, natalizumab treated patients as well as HIV patients, John Cunnigham (JC) virus reactivation in the CNS often leads to progressive multifocal leukoencephalopathy (PML), indicating that the impact on the immune system with an inverse CSF CD4+/CD8+ ratio might have similar effects on certain opportunistic infections. Here, CD4 is linked to progressive multifocal leukoencephalopathy.