Inhibitory Effect of Gamma Interferon on BK Virus Gene Expression and Replication

Abstract

Polyomavirus nephropathy (PVN) results in renal dysfunction and graft loss in up to 10% of all kidney transplant recipients (18). It is widely accepted that BK virus (BKV) is the etiological agent responsible for the majority of cases of PVN, which are typically diagnosed within the first year after transplantation (19,20). PVN is characterized by the lytic, destructive replication of BKV in proximal tubule epithelial cells in the transplanted kidney and is normally diagnosed by renal biopsy to assess histological effects of infection, PCR to determine viral presence and loads in the urine and blood, and the detection of decoy cells, which are cells with distinct intranuclear inclusion bodies that are shed during active BKV replication, in the urine (reviewed in references 10, 17, and 30). Since there are currently no effective antiviral treatments for BKV infection, the most common approach used to control PVN is to decrease the patient's immunosuppressive regimen. However, such an approach increases the risk of graft rejection and thus is not an appealing strategy. The prevalence of PVN is increasing with the advent of new, more powerful immunosuppressive therapies, making it a growing concern for the transplant community.The human polyomavirus BKV was first isolated in 1971 in the urine of a renal transplant recipient (11). BKV virions are small (40 to 45 nm in diameter), nonenveloped, and icosahedral and contain a circular, double-stranded DNA genome of approximately 5.2 kb (reviewed in reference 29) which is associated with cellular histones to form a chromatin-like structure (28). The genome encodes only six known proteins: the early proteins, large tumor antigen (TAg) and small tumor antigen, and the late proteins, VP1, VP2, VP3, and agnoprotein. BKV infects nearly the entire population, with seroprevalence reaching 60 to 80% by the age of 10 (reviewed in reference 23). BKV is thought to be contracted by respiratory transmission, and the primary infection is typically subclinical. Following the initial infection, BKV spreads to other cells of the body, most notably peripheral blood mononuclear cells (9) and cells of the kidney and urinary tract (4,16,39), in which the virus establishes a persistent, subclinical infection. It is at these sites in immunocompromised patients that BKV reactivates to a lytic infection, resulting in BKV-associated diseases, such as PVN.Previously, we described an in vitro system that allows the study of BKV lytic infection of primary human proximal tubule epithelial cells (27). The functions of proximal tubule cells in the kidney include facilitation of the recovery of blood products, maintenance of blood pressure and volume, and production and release of cytokines and chemokines to communicate with the host immune system (2, 6). Proximal tubule cells remain in a differentiated state for up to six passages in tissue culture (21) and thus provide an environment similar to that which BKV encounters in an immunocompromised host. By introducing individual elements of the immune sys...

Type I and II IFNs Inhibit Merkel Cell Carcinoma via Modulation of the Merkel Cell Polyomavirus T Antigens

“…It should be further noted, that specific miRNAs have been suggested to be involved in MCV virion release (34). As mentioned earlier, recent reports described that IFN-g treatment interferes with LTA expression in BK virus-infected cells (20) and that type I IFNs interfere with LTA expression in JC virus-infected cells (19). (21).…”

“…In this regard, type I IFNs can both limit the replication of John Cunningham (JC) virus and interfere with expression of virally encoded genes (19). Similarly, IFN-g is able to suppress BK virus gene expression (20 …”

miRNA regulation of BK polyomavirus replication during early infection

“…Primary human RPTE cells (Lonza) were maintained in renal epithelial growth medium (REGM) for up to six passages (26). 293TT cells were obtained from Chris Buck at the National Cancer Institute and were maintained under 400 μg/mL hygromycin selection (27).…”

Host-Specific Replication of BK Virus DNA in Mouse Cell Extracts Is Independently Controlled by DNA Polymerase α-Primase and Inhibitory Activities

“…As with other members of the Polyomaviridae family, BKV virions are nonenveloped icosahedral particles with a diameter of 45 nm that contain a circular double-stranded DNA genome of 5.3 kb (1). In BKV and in other polyomaviruses, three genomic areas have been distinguished: (i) a noncoding control region including the origin of viral DNA replication, (ii) the early genes encoding large and small T antigens (TAgs), and (iii) the late genes which code for the capsid proteins VP-1, VP-2, and VP-3 and the agnoprotein (22).…”