ReviewHuman polyoma viruses and disease with emphasis on clinical BK and JC
Introduction
The first polyoma virus, Murine K virus, was described by Kilham in 1952.1 Subsequently, Gross identified the mouse polyoma virus (MPyV) producing small tumors in newborn mice.2 He inoculated murine leukemia virus into newborn mice producing leukemia and parotid adenocarcinomas. Cell free extracts from the parotid glands produced a variety of solid tumors. These viruses were later named by Stewart et al. as polyoma virus in 1958 as they have propensity to produce a variety of solid tumors in newborn mice.3, 4 Simian polyoma virus, simian vacuolating virus (SV40), which infects rhesus monkeys was identified by Eddy et al., as the contaminant of Salk human polio vaccine.5 Padgett et al. identified JC virus (JCV) as the infective agent in a patient, John Cunningham (initials JC), with Hodgkin's lymphoma who suffered from progressive multifocal leukoencephalopathy (PML) in 1971.6 During the same year, BK virus (BKV) was isolated by Gardner from urine of a Sudanese kidney transplant patient with ureteric stenosis whose initials were BK.7
KI polyoma virus (KIPyV) and WU polyoma viruses (WUPyV) were identified in 2007 from respiratory secretions of patients with respiratory infections by Allander and Gaynor et al., respectively.8, 9 KI and WU viruses are named after the institutions where they were initially isolated. In January 2008, Feng et al., identified Merkel cell polyoma virus (MCPyV) which has been associated with Merkel cell carcinoma.10 With the identification of the MCPyV, currently, known polyoma viruses include 16 different viral species and infect 8 different mammalian species10, 11 (Fig. 1). Natural hosts for these viruses are humans, monkeys, rodents, cattle, rabbits and birds. These viruses are fairly species specific and do not readily infect other species.12 The two viruses that can cause significant diseases in humans are BK virus which causes an interstitial nephritis, known as BK virus nephropathy (BKVN) or polyoma virus associated nephropathy (PVAN) and JC virus which causes PML in AIDS and other immunosuppressed patients. We review the biology, life cycle, and epidemiology of the human polyoma viruses in general and focus on the diagnosis and management of BK and JC disease.
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Biology of polyoma viruses
The genus of polyoma viruses belongs to the Papovavirdae family. Polyoma viruses are icosahedral, non-enveloped double stranded circular super coiled viruses. They measure 40.5–44 nm in diameter and comprise 88% protein and 12% DNA.13 The viral DNA genome has around 5000 base pairs organized in three different functional regions: the early coding and late coding regions separated by a non-coding regulatory region (NCCR).12, 14, 15 The NCCR encompasses the origin of DNA replication (ori) and has
Polyoma virus life cycle
Each virus requires a specific receptor for cellular entry, which explains their tissue tropism and species specificity. SV40 uses the ganglioside GM1 and a receptor that belongs to the MHC class I protein.11, 25 BK uses an N-linked glycoprotein containing alpha (2,3) linked sialic acid, GT1b, GD1b whereas MPyV uses GD1a and GT1b as the receptors.26, 27, 28 Cells treated with neuroaminidase limit BKV infection in vitro. The JC virus uses alpha (2,6) linked sialic acid associated with the
Epidemiology of polyoma viruses
The prevalence of BK and JC viral infection differs in geographical and age distribution suggesting they circulate independently.39 BK infection is acquired in early childhood whereas JC presents later, 3–4 years versus 10–14 years.40, 41, 42 Approximately 80% of the adult population is seroprevalent for polyoma viruses.40, 41, 42 The mode of transmission of these viruses is not well known. Transmission through the feco-oral and respiratory routes has been suggested.43, 44 Other routes include
Clinical diseases
After initial infection, both BK and JC viruses remain latent in different tissues (vide infra). For unknown reasons, BK viruria correlates with degree of immunosuppression whereas JC viruria does not. BK virus can cause pneumonitis, hepatitis, retinitis, and meningoencephalitis.52 Hemorrhagic cystitis from BK virus is seen in 25–60% of the bone marrow transplant patients (BMT).53, 54, 55 It is usually seen 2 weeks after transplant which is later than the hemorrhagic cystitis from
BKV nephropathy
After primary infection in childhood BK virus becomes latent in the tubular epithelial cells of the urogenital tract.51 It mainly affects epithelial cells of collecting ducts, tubular epithelium of renal calyces and renal pelvis.60 In immunosuppressed states BK may reactivate in the renal tubular epithelial cells causing necrosis and lytic destruction with denudation of the basement membrane allowing tubular fluid to accumulate in the interstitial compartment, which in turn causes interstitial
Progressive multifocal leukoencephalopathy (PML)
Progressive multifocal leukoencephalopathy is a progressive demyelinating central nervous system disorder involving cerebral white matter caused by the JC virus81. It most often presents as an opportunistic infection in HIV patients with lymphopenia but has recently been seen with new immunosuppressives (vide infra). Typical PML patients have very low CD4 T-cell counts even less than 200/mm2. PML also seen in other immunosuppressed states such as myeloproliferative and lymphoproliferative
BK
A diagnosis of BKVN requires a biopsy but can be suggested or supported by detection of viral replication in urine or blood. Urine of patients’ with BKVN may show “Decoy cells” which are infected renal tubular epithelial cells with intranuclear basophilic inclusion bodies seen on Papanicolaou stain.51, 94 Decoy cells have 100% sensitivity but a positive predictive value of only 20%.62, 95 BK viral replication can be documented by urine or blood BK viral DNA polymerase chain reaction (PCR) or
BK
The first line of treatment of BK virus nephropathy is reduction of immunosuppression.51, 71 There are no fixed guidelines for the reduction of immunosuppression as there are only a few controlled studies. We have shown that immediate withdrawal of the anti-metabolite upon detection of BK viremia is a safe and effective preemptive strategy to prevent progression from viremia to clinical nephropathy without increasing the risks for acute rejection.68 Ancillary therapy with antiviral agents is
Role of polyoma virus in malignancy
As above, there may be a role for polyoma viruses in human malignancy. Polyoma viruses produce tumors in rodents and transform cell lines, and polyoma proteins have been identified in several different human cancers. Polyoma viral proteins interact with regulatory proteins such as p53 and pRb, cyclins, and cyclin dependent kinases.110 However the exact causative and oncologic potential to humans except for Merkel Cell tumor is controversial in the recent literature.
Summary
Polyoma viruses are widespread and affect 80% of the human population. They do not cause clinically significant infections in immunocompetent hosts. The two most common polyoma viruses that cause clinically significant diseases in humans are JCV causing PML and BKV causing BKVN. Further studies are needed to firmly establish the role of polyoma viruses in human cancer. There is no known effective antiviral agent although two new trials which hold promise are just beginning.
Acknowledgments
This work was supported in part by NIH 2 K24-02886 (DCB) and DK 07933 (DCB).
Conflict of interest: none.
Ethical approval: not required.
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