Papovaviruses in Relation to Human Disease

29 May

As noted in Table 12.7, herpes, hepatitis, and papilloma viruses constitute the major infectious causes of human neoplasms. However, the search for papovaviruses as etiological agents in hu- man neoplasia was pursued intensively for several decades. The first indication for a role of pa- povaviruses in human disease was the observation by Zu Rhein and Chou (1965) of the presence of papovavirus-like  particles in the nuclei of glial cells from patients with a rare demyelinating disease, progressive multifocal leukoencephalopathy  (PML). Later studies by these workers and their colleagues (Padgett et al., 1971) allowed the cultivation of papovaviruses from the brain of a patient with PML. Subsequently, this virus has been termed the JC virus, and it is closely re- lated to other papovaviruses  such as the simian virus 40. The majority of patients with PML exhibit some impairment of the T-cell immune response (Chapter 18). As many as 4% of pa- tients with AIDS will have PML, while up to 85% of all new cases of PML will have AIDS (cf. Tornatore et al., 1994). In PML, the JC virus infects oligodendrogliocytes,  cells responsible for the myelination of nerve axons in the central nervous system. Destruction of these cells leads to

Figure 12.19 Model of the pathogenesis  of Kaposi sarcoma. bFGF, basic fibroblast growth factor; IL, interleukin; KSHV, Kaposi sarcoma–associated herpesvirus; Onco M, oncostatin M; TNF-α,  tumor necro- sis factor-alpha. (From Emmanoulides  et al., 1996, with permission of the authors and publisher.)

the loss of myelin in axons and disruption  of normal function in the central nervous system (Aksamit, 1995).

The JC virus also induces a variety of neoplasms in rodents, especially hamsters, and can also infect a variety of cultured cells (Zu Rhein, 1987; cf. Major et al., 1992). In addition, brain tumors have been induced in monkeys inoculated  with the JC virus (London et al., 1978). A closely related virus, the BK virus, is commonly present in normal individuals, but there is little or no evidence that the virus is involved in the causation of human disease (Wold et al., 1978). However, a recent study by Flægstad et al. (1999) detected BK virus DNA in all of a series of 18 human neuroblastomas.

In support of a potential role for papovaviruses  in the causation of specific human neo- plasms, some evidence has been reported for the presence of simian virus 40 DNA in several different types of human brain neoplasms (Krieg et al., 1981; Bergsagel et al., 1992; Martini et al., 1996) and in malignant mesotheliomas (Testa et al., 1998). At least one group (Bergsagel et al., 1992) has suggested that there may be a causal relationship between these viruses and the genesis of these brain tumors involving  papovavirus  genomes  present in those human neo- plasms. One possible source of infection is suggested to be through inadvertent inoculation of humans with the simian virus 40 that had contaminated vaccines against other viruses used be- tween 1955 and 1963 (Carbone et al., 1997). However, Strickler et al. (1998) reported an exten- sive retrospective epidemiologic  study that showed no association between exposure to simian virus 40-contaminated  poliovirus vaccine and increased rates of brain neoplasms, sarcomas, or mesotheliomas.

Although the JC and BK virus, when infecting rodent cells, become incorporated into the DNA with subsequent transformation to the neoplastic state (cf. Major et al., 1992), JC virus in brains and kidneys of patients with PML is not integrated into the host cell genome (Grinnell et al., 1983). Thus, while there is no question that the JC virus causes PML, the relation, if any, of papovaviruses  to the causation of human neoplasia remains an unanswered question with rela- tively little supporting data for such an association at the present time.

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