Is JC Virus latent in brain?

Progressive multifocal leukoencephalopathy (PML) was first recognized as a distinct neuropathological entity in 1958 El]. The disease is characterized by progressive demyelinating lesions in brain secondary to an opportunistic virus infection and impaired cellular immunity. PML was originally described in patients with chronic diseases, such as lymphoma, leukemia, sarcoidosis, tuberculosis, and carcinomatosis, and recipients of organ transplants receiving immunosuppressive agents. Once a rare disease, PML has become relatively common as a result of the epidemic of acquired immunodeficiency syndrome (AIDS). The estimated incidence of PML among AIDS patients is approximately 4.0%, which is far greater than previously experienced 12). Therefore, as many as 6,000 cases of PML may be expected to develop among the 15 5,000 persons in the United States who have already contracted AIDS. The ability of long-term antiviral chemotherapy with agents such as zidovudine (formerly azidothymidine [AZT]) to prolong the life of the patient and the course of AIDS could lead to an even higher incidence of PML. Perhaps it is because of their profound immunosuppression or younger age that AIDS patients are experiencing a considerable increase in the incidence of PML. The mean age of 16 AIDS patients with PML in one report 121 was 36 years, compared to a peak onset in the sixth decade for PML in patients without AIDS 131. What conditional impact age might have on the development of PML is unknown. Only minor neuropathological differences in PML patients with AIDS compared to those without AIDS have been reported 141. No evidence was found of productive infection in macrophages and mononuclear cells known to harbor the human immunodeficiency virus [4}, so that synergistic effects of the two viruses from coinfection of the same cell as has been suggested seems unlikely. Although PML is more frequent in the AIDS population, the course and severity of PML in patients with and without AIDS is similar. It seems likely that the practicing neurologist will encounter PML more frequently in the future. In the mid-l960s, the viral cause of PML was discovered by electron microscopy of PML lesions, which revealed typical papovavirus particles in the nuclei of abnormal oligodendrocytes. Papovaviruses consist of two different groups, the papilloma viruses and the polyoma-vacuolating viruses, which have similar morphology but are different in size. Several years passed before Padgett and co-workers 151 isolated and characterized a new polyomavirus, designated JC virus, from the brain of a patient with PML. Except for two early isolates of simian virus 40 (SV40) from PML which were probably contaminants from the monkey kidney cell line employed, all subsequent PML isolates have turned out to resemble JC virus. JC virus replicates selectively in brain only in oligodendrocytes and astrocytes. Destruction of oligodendrocytes results in primary demyelination. Serological surveys have shown that seroconversion to JC virus occurs during childhood in the majority of the population worldwide 161; however, primary infection with this virus is not implicated as the cause of any childhood illness. Apparently, only during chronic immunosuppression does JC virus become pathogenic, and then it only causes PML. Current belief holds that JC virus induces PML when reactivated from a latent state during immunosuppression and not through primary infection. The kidney is the recognized site of latent JC virus infection. During pregnancy as well as in bone marrow and renal transplantation, JC virus may be shed in the urine. During immunosuppression JC virus may then disseminate through the bloodstream to the brain and occasionally to the lung and lymphoreticular organs (B cells) 17). The facts that PML often begins unifocally in brain and that lesions tend to concentrate at the gray-white matter junction where endarterioles terminate are consistent with the notion of hematogenous spread. Nucleotide sequence data from brain and kidney isolates from the same patient have provided evidence for the identity of the virus from both tissues but also revealed variations in the transcriptional control elements {S]. Transcriptional control elements are responsible for tissue-specific expression of JC virus and probably account for its extremely restricted host range. Hence, mutations or rearrangements in the control elements of JC virus reactivated in the kidney may be responsible for its successful spread to and growth in brain cells. Whether JC virus also remains latent in brain is unclear. A small number of reported cases of primary PML with a prolonged clinical course but without immunosuppression support latency in the brain. Previous attempts at JC virus detection in brain by hybridization have not revealed latent virus. The report by Mori and colleagues 191 in this issue of Annals may shed new light on this question. Using the techniques of in situ hybridization and immunohistochemistry to detect JC virus, they found viral DNA and protein at autopsy in a limited number of oligodendrocytes and astrocytes in 4 of 10 brains of elderly patients without