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Parmjeet Randhawa MD.

Departments of Pathology. University of Pittsburgh School of Medicine. Pittsburgh, Pennsylvania. USA


Biology & genomic organization of polyoma viruses:

Polyomaviruses are 45nm sized particle with a 5 kb genome 1, 2 The viral genome averages 5 kilobases in length, and is comprised of double-stranded circular supercoiled DNA. The viral genome is typically arranged in three general regions: non-coding control region (NCCR), the early coding region coding for the small and large T antigens, and the late coding region coding for the viral capsid proteins (VP-1, VP-2, VP-3) and agnoprotein. The direction of early and late transcription is divergent, with opposite DNA strands participating in these processes3.

The NCCR contains (a) the origin of replication (ori), and (b) regulatory regions containing enhancer elements that are important activators of viral transcription 4. Naturally occurring BKV and JCV strains in the kidney and urine usually have an archetypal regulatory region, although this in not an invariable rule 5, 6. By contrast, JCV found in the brain tissue of patients with progressive multifocal leucoencephalopathy (PML) usually shows a variety of genetic mutations & rearrangements 7-9. There is in-vitro evidence that NCCR variants determine host cell permissivity and rate of viral replication 9, 10. Hence, genetic rearrangements are believed to be critical in permitting viral transcription in the brain, which ultimately culminates in the pathologic lesions of progressive multifocal leucoencephalopathy. Such rearrangements have been described in isolated case reports of immunodeficient individuals with BKV infection, but are present only in a small proportion of patients with BKV nephropathy.

The T antigens bind to tumor suppressor proteins Rb and p53 and stimulate host cell entry into the cell cycle 13, 14. This observation provides a theoretical basis for multiple lines of accumulating evidence that PV may be carcinogenic in man:

    (a). PV can transform fibroblast cell lines and is a well established carcinogen in experimental animals 3, 15,
    (b) BKV DNA has been found in renal cell carcinoma and urothelial carcinoma 16-18,
    (c) Glial tumors contain JCV DNA, and infectious JCV has been recovered from a patient with a choroid plexus tumor3,
    (d) SV40 DNA has been repeatedly found in human tumors (see section B.2.), and
    (e) mesothelioma tissue has been found to contain functionally active SV40 T-antigen capable of binding to the tumor suppressor protein p53 13, 19-21.

Nonetheless, the idea that PV can cause human cancer remains unproven because of the ubiquitous latency of this group of viruses.

The viral capsid proteins VP-1, VP-2, and VP-3 are structural proteins required for the assembly of complete virions. The viral capsid coding regions display considerable genetic heterogeneity, and this feature has been used to divide BKV into distinct genotypes I, II, III, and IV 22-26, and JCV into Types 1, 2A, 2B, and 3-8 27-33. In mice, specific mutations in the viral capsid protein VP-1 region have been associated with increased viral pathogenicity 34, 35. Whether similar considerations apply to human patients with BKV associated renal allograft interstitial nephritis is unknown. The existence of potential relationships between viral genotype and clinical virulence is illustrated by the observation that progressive multifocal leukoencephalopathy is associated primarily with JCV Type 2B infection.

Agnoprotein protein localizes primarily to the cytoplasmic and perinuclear regions of the host cell. This distribution has led to the suggestion that agnoprotein may promote virion release from cell 36. Other proposed roles for this protein include participation in host cell lysis, enhanced nuclear localization of viral capsid protein VP-1, and help in viral capsid assembly 37. Cultured cells infected with agnogene mutants show a 17-100 fold reduction in virion burst size 38. JCV agnoprotein has recently been localized in medulloblstoma 39. No data is currently available on the occurrence of mutant agnoproteins in human disease. An overview of the clinical aspects of PV infections in man follows. The emphasis is on BKV, which is currently believed to be the principal etiologic agent of renal disease in immunosuppressed individuals. However, simian polyoma virus SV40 and JCV will also be discussed briefly.

SV40 infections in man:

SV40 is a simian virus, which causes a disease resembling progressive multifocal leucoencephalopathy in immunocompromised monkeys. The use of live vaccines prepared in monkey cells led to about 10-30 million human beings getting infected by this virus between 1954 and 1963 3, 40. There are now increasing reports documenting authentic SV40 sequences in a variety of human neoplasms, including mesothelioma, choroid plexus papilloma, ependymoma, non-Hodgkin lymphomas, and osteogenic sarcomas20, 41-46. Viral sequences have been found in leucocytes of healthy blood donors, and native kidneys with focal segmental sclerosis, minimal change disease, and membranous glomerulopathy 47. Simian polyoma virus SV40 sequences have recently been documented in healthy kidney transplant recipients 48, and in the blood and urine of patients with PVAN . A pathogenic role for SV40 in viral nephropathy has not yet been established, but this is an area which needs more systematic investigation.

JCV infections in man:

JCV was initially isolated from a patient with PML, and can be found in up to 75% of blood & 92% of cerebrospinal fluid samples obtained from these patients 49-52. Subsequent studies showed widespread serologic evidence of infection in human populations 53. Following primary infection, the virus becomes latent in the kidney and B-lymphocytes 54-56. JCV can be excreted with significant frequency in the urine of healthy individuals 29, 32, 57, 58. Unlike BKV, some studies have failed to find a correlation between the frequency of JCV viruria and the degree of immunosuppression 59-61. However, PML occurs primarily in the setting of immune deficiency, such as in patients with AIDS, solid organ transplantation, lymphoproliferative disorders, neoplastic diseases, myeloproliferative syndromes, and sarcoidosis 53, 62, 63.

Although type 2 is the most common genotype associated with PML, type 1 cases have also been reported 64. It is not certain whether JC virus can cause renal disease. However, we have found JCV DNA to be present in 7/19 (37%) renal allograft biopsies with BKV associated PVAN 65. The frequency of JCV in allograft biopsies appears to be higher than that observed in native and allograft kidneys without polyomavirus nephropathy (PVAN), where it was found in 0/19 (0%) samples. Studies of JCV gene expression and genomic mutations in allograft kidney tissue are needed further evaluate a potential role of JCV in causing renal allograft dysfunction in man.

BKV infections in man:

BKV was first isolated in 1970, & subsequent studies documented a world-wide seroprevalence rate of 60-80% 1, 2, 66. Initial infections usually occur in childhood putatively via the respiratory route, followed by viral latency in the urogenital tract. BKV reactivation with urinary shedding of infected urothelial cells is recognized to occur in 10-60% of renal transplant recipients. Receipt of a kidney from a seropositive donor is a risk factor for lytic infection regardless of the serologic status of the recipient at the time of transplantation 1, 2.

Most early studies found only sporadic cases of graft dysfunction associated with viral activation, and did not report any biopsy findings 67-69. BKV-associated interstitial nephritis associated with serious graft dysfunction was initially described in the setting of congenital immunodeficiency and AIDS 70, 71. More recent studies have shown that BK virus can cause PVAN in up to 8% of renal allografts 17, 72-79.

Typically, a diagnosis of BKV associated PVAN is made by recognition of viral inclusions in renal tubular and glomerular epithelial cells at allograft biopsy. Viral inclusions are associated with variable mononuclear interstitial infiltrates and focal tubulitis that closely resembles acute rejection. It is not known if this resemblance reflects common mechanisms of T-cell influx, or the concurrent presence of viral infection and true acute rejection. The relationship between PV infection and acute as well as chronic graft rejection remains to be evaluated in a systematic fashion, as has been done for cytomegalovirus 80, 81 Conceivably, PV infection could precipitate acute rejection via upregulation of MHC class I or class II antigen expression, or the release of other pro-inflammatory cytokines. However, the cytokine milieu associated with human PVAN has not been specifically investigated. Conversely, experimental evidence suggests that tubular injury associated with acute cellular rejection could secondarily increase PV replication 82. In approximately 30% of the biopsies with PVAN, a significant inflammatory infiltrate of polymorphs is also present. Prominence of plasma cells and changes resembling acute tubular necrosis are other histomorphologic features described in this clinical setting.

Although, a definitive diagnosis of PVAN currently requires a biopsy, there is considerable interest in developing less invasive diagnostic methods. It has been found that on urine cytology, most cases with detectable viral inclusions are asymptomatic, but presence of >10 inclusion bearing cells with an accompanying inflammatory response identifies all cases of PVAN 76. Urine viral load > 1E+07 copies/ml and plasma viral load > 1E+04 copies/ml tends to correlate with histologic nephropathy, but a biopsy is needed for definitive diagnosis.

Clinical management of BKV renal allograft nephropathy remains a significant challenge. Even when biopsies show tubulitis suggesting the possibility of underlying rejection, there is little or only transient response to corticosteroids in most cases. Conversely, reducing immunosuppression decreases the viral load, but increases the risk of rejection. This therapeutic dilemma results in an unfavorable graft outcome, which is unlikely to improve till clinically effective anti-polyomavirus drugs are developed. No clinically proven anti-PV drugs are currently available for the management of PVAN.

However, we have had encouraging results with cidofovir, which typically results in clearance of viremia, and several log reduction in the urinary titers of virus 86. Controlled trials need to be performed to better substantiate the efficacy of this drug. Less nephrotoxic antiviral compounds also need to be evaluated for potential clinical use. For example, retinoic acid derivatives, nalidixic acid and oxolinic acid suppress replication and cytopathic effect of BKV in vitro87, 88.

Topoisomerase inhibitors block JCV replication in fetal glial cells and have had variable success in the therapy of patients with PML 89. Lefunomide is another drug that has been recently used in BKV nephropathy 90.

Figure 1:
Immunoperoxidase staining showing viral T-antigen expression in a biopsy with BKV nephropathy. Strong nuclear reaction is seen in several tubular epithelial cells. A brisk mononuclear cell infiltrate is seen in the interstitial compartment.


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