In their seminal report in 1958, Astrom, Mancall, and Richardson described a progressive neurologic syndrome with a characteristic triad of neuropathologic findings, namely, demyelination, giant astrocytes, and oligodendrocytes with abnormal nuclei. They named the disorder progressive multifocal leukoencephalopathy (PML). The viral etiology of this neurologic disease was not determined until later. Until the advent of the acquired immunodeficiency syndrome (AIDS) pandemic, PML remained a vanishingly rare disorder seen almost exclusively in individuals with underlying immunosuppressive disorders. Prior to the advent of highly active antiretroviral therapy (HAART), PML occurred in approximately 1 in 20 of all human immunodeficiency virus (HIV)-infected persons in developed countries. Although the incidence of AIDS-associated PML appears to have declined since the availability of HAART, it has not declined to the extent observed with other opportunistic infections (Sacktor 2002). Currently, AIDS has been estimated to be the predisposing disorder for about 90% of all PML cases. More recently, monoclonal antibodies, such as natalizumab, an α4 β1 integrin inhibitor, and rituximab, a chimeric monoclonal antibody directed against CD20 receptors on B cells, and other immune-altering pharmacologic agents, such as mycophenolate mofetil, have been associated with PML and carry US Food and Drug Administration (FDA) mandated “black box” warnings of this risk.
JC virus and the pathogenesis of PML
In 1965, Zu Rhein and Chou identified viral particles in glial nuclei resembling papovavirus. Subsequently, Padgett isolated polyomavirus from PML brain in glial cell cultures. The virus has a simple DNA genome of 5.1 kilobases in a double-stranded, supercoiled form, encapsidated in an icosahedral protein structure measuring 40 to 50 nm in diameter. The virus was named the JC virus (JCV) after the initials of the person from whom it was first isolated. JCJCV DNA encodes for three capsid (VP1, VP2, and VP3) proteins and five regulatory proteins (agnoprotein, t, T, T, T’135, T’136, and T’165); the latter three are derived by alternative splicing of early viral mRNA. To date, all cases of PML have been associated with JCV; although there are rare reports of other polyomaviruses, in particular, BK virus, being associated with PML-like disorder in immunosuppressed individuals.