The dramatic increase in the incidence of
progressive multifocal leukoencephalopathy (PML) that occurred as a consequence of the
AIDS pandemic and the recent association of PML with the administration of
natalizumab, a
monoclonal antibody to
alpha4 integrin that blocks inflammatory cell entry into the brain, has stimulated a great deal of interest in this previously obscure viral
demyelinating disease. The etiology of this disorder is JC virus (JCV), a polyoma virus, observed in 80% of the population worldwide. Seroepidemiological studies indicate that
infection with this virus typically occurs before the age of 20 years. No primary illness owing to JCV
infection has been recognized and the means of spread from person to person remains obscure. Following
infection, the virus becomes latent in bone marrow, spleen, tonsils and other tissues. Periodically the virus reactivates during which time it can be demonstrated in circulating peripheral lymphocytes. The latter is significantly more commonly observed in immunosuppressed populations than that in normal subjects. Despite the large pool of people infected with JCV, PML remains a relatively
rare disease. It is seldom observed in the absence of an underlying predisposing illness, typically one that results in impaired cellular immunity. A variety of factors are likely responsible for the unique increase in frequency of PML in
HIV infection relative to other underling immunosuppressive disorders. Preliminary data suggests that
natalizumab appears to distinctively predispose recipients to PML relative to other infectious complications. Studies in these populations will be invaluable in understanding the mechanisms of disease pathogenesis.