Gregory A. Storch
The polyomaviruses are small (45 nm), nonenveloped, circular, double-stranded DNA viruses with genomes of approximately 5,000 bp. Because of the association of animal polyomaviruses with tumors in the animals they infect, there has been concern for a relationship to neoplasia in humans; however, there is strong evidence for an etiologic role in neoplasia only for Merkel cell polyomavirus (see below). Among the other polyomaviruses, the traditional human pathogens are JC virus and BK virus. The number of human polyomaviruses has expanded dramatically, with discovery of up to 12 additional viruses. Two polyomaviruses, designated KI virus and WU virus, can be detected in respiratory samples from children; however, a pathogenic role for these viruses has not been proven to date. Merkel cell polyomavirus is associated with Merkel cell carcinoma, an unusual neuroectodermal tumor of the skin that occurs primarily in elderly and immunocompromised individuals. Clonal integration of Merkel cell polyomavirus DNA is present in Merkel cell carcinoma cells, supporting an etiologic role for the virus in the development of the tumor. Another human polyomavirus has been isolated from patients with the dermatologic condition trichodysplasia spinulosa and has been named trichodysplasia spinulosa–associated polyomavirus. Trichodysplasia spinulosa is a condition of the skin that occurs in immunocompromised individuals and involves the development of follicular papules and keratin spines, usually involving the face. Two other viruses, designated human polyomaviruses 6 and 7, have also been found in human skin samples. They have been implicated in pruritic skin rashes in immunocompromised individuals. Human polyomavirus 9 was detected in serum from a renal transplant recipient. Other recently discovered viruses, named Malawi virus and St. Louis virus, were first detected in stool samples, but a role in gastrointestinal or other disease has not been established at this time.
JC and BK viruses are tropic for renal epithelium; JC virus also infects brain oligodendrocytes and is the etiologic agent of progressive multifocal leukoencephalopathy (PML), a rare and often fatal demyelinating disease of immunocompromised persons, especially those with AIDS. PML is known to occur in individuals receiving the immunomodulatory agents natalizumab (Tysabri), used to treat multiple sclerosis and Crohn disease, efalizumab (Raptiva), used to treat psoriasis, the anti-CD20 monoclonal antibody rituximab (Rituxan), and the anti-CD52 monoclonal antibody alemtuzumab (Campath), as well as multiple other immunomodulatory agents. BK virus is the cause of transplant nephropathy in renal transplant recipients and of hemorrhagic cystitis in hematopoietic stem cell and bone marrow transplant recipients. Several million persons in the United States were exposed to simian virus 40 (SV40), an oncogenic polyomavirus of Asian macaques, from contaminated poliovirus vaccines administered during the years 1955 to 1963. There were no recognized sequelae and no demonstrable increased risk for cancer.
Seroepidemiologic studies have shown that infection with all of the human polyomaviruses appears to be widespread, often occurring during childhood. Primary infection with these viruses is not recognized clinically. Approximately half of children in the United States are infected with BK virus by 3-4 yr of age and with JC virus by 10-14 yr of age, and approximately 60–80% of adults are seropositive for one or both viruses. Infection with polyomaviruses is thought to persist throughout life, with JC and BK viruses remaining latent in renal epithelium, oligodendrocytes, and peripheral blood mononuclear cells. The site of latency of the other human polyomaviruses is not currently known. Approximately 30–50% of healthy persons have detectable BK or JC virus in renal tissue at autopsy. Reactivation and viruria occur with increased frequency with advancing age and are more common in immunocompromised persons. On the basis of polymerase chain reaction results, BK and JC viruria occurs in 2.6% and 13.2%, respectively, of persons younger than 30 yr of age and in approximately 9% and 50%, respectively, of persons older than 60 yr of age.
Reactivation of BK and JC viruses with asymptomatic viruria occurs in 10–50% of hematopoietic stem cell and bone marrow transplant recipients and in 30% of renal transplant recipients. Of those renal transplant recipients who demonstrate BK viruria, approximately one third also have plasma viremia. Recipients with plasma viremia are at risk for development of nephropathy, which can clinically mimic allograft rejection and can result in failure of the allograft. Reduction of immunosuppression has been effective in preventing progression from viremia to nephropathy, and thus posttransplantation monitoring of either urine or plasma by polymerase chain reaction is important. It is particularly important to distinguish BK nephropathy from rejection because the treatments are different—increase in immunosuppression for rejection but decrease in immunosuppression for BK nephropathy.
Polymerase chain reaction is the preferred means for detecting the BK and JC viruses. The high seroprevalence in the general population and lack of clear relationship to clinical illness limit the usefulness of serologic testing, although recent studies suggest that high levels of anti-BK antibodies in renal transplant donors are associated with an increased risk of BK disease in the recipient. There are no proven antiviral treatments for BK or JC virus infection, although cidofovir may be effective in some cases of BK-related transplant nephropathy. Effective treatment of AIDS with antiretroviral therapy can prevent the progression of progressive multifocal leukoencephalopathy. Allogeneic BK virus–specific T cells are a potentially beneficial therapy for PML.