A review on JC virus infection in kidney transplant recipients.

Hindawi Publishing Corporation Clinical and Developmental Immunology Volume 2013, Article ID 926391, 7 pages http://dx.doi.org/10.1155/2013/926391 Review Article A Review on JC Virus Infection in Kidney Transplant Recipients Serena Delbue,1 Mariano Ferraresso,2,3 Luciana Ghio,4 Camilla Carloni,5 Silvia Carluccio,5 Mirco Belingheri,4 Alberto Edefonti,4 and Pasquale Ferrante5,6 1 Laboratory of Translational Research, Health Science Foundation “Ettore Sansavini”, Corso Garibaldi 11, 48022 Lugo, Italy Department of General and Vascular Surgery, St. Joseph Hospital, Via San Vittore 12, 20122 Milan, Italy 3 Department of Clinical Sciences and Community Health, University of Milan, Via Francesco Sforza 35, 20122 Milan, Italy 4 Pediatric Nephrology and Dialysis Unit, IRCCS Ca’ Granda Foundation “Ospedale Maggiore Policlinico”, Via Francesco Sforza 35, 20122 Milan, Italy 5 Laboratory of Translational Research, Department of Biomedical, Surgical and Dental Sciences, University of Milan, Via Pascal 36, 20133 Milan, Italy 6 Clinical Institute “Città Studi”, Via Ampere 47, 20133 Milan, Italy 2 Correspondence should be addressed to Mariano Ferraresso; Received 2 August 2012; Revised 3 January 2013; Accepted 3 January 2013 Academic Editor: Hans Hellmut Hirsch Copyright © 2013 Serena Delbue et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. The polyomavirus (PyV), JC virus (JCV), is a small nonenveloped DNA virus that asymptomatically infects about 80% of healthy adults and establishes latency in the kidney tissue. In case of immunodeficient hosts, JCV can lytically infect the oligodendrocytes, causing a fatal demyelinating disease, known as progressive multifocal leukoencephalopathy (PML). Although the reactivation of another human PyV, BK virus (BKV), is relatively common and its association with the polyomavirus associated nephropathy (PyVAN) following renal transplantation is proven, JCV replication and its impact on graft function and survival are less well studied. Here we describe the biology of JCV and its pathological features and we review the literature regarding the JCV infection analyzed in the setting of transplantations. 1. An Introduction to the Human Polyomavirus JC (JCV) JC virus (JCV) is a member of the Polyomaviridae family, including naked DNA viruses with icosahedral capsids and small, circular, and double-stranded DNA genomes. The natural hosts for polyomaviruses (PyVs) include humans, other primates, rodents, rabbits, and birds [1]. It was first isolated by Padgett et al. in 1971 from the brain of a patient with the initial JC, affected by Hodgkin’s lymphoma who died of progressive multifocal leukoencephalopathy (PML), a demyelinating disease of the central nervous system (CNS) [2]. The 40–45 nm capsid is composed of three structural viral proteins, VP1, VP2, and VP3. The icosahedron consists of 72 pentamers, with no apparent hexamers, each composed by five VP1 molecules and one molecule of VP2 or VP3. The virion is formed of 88% protein and 12% DNA, represented by a single copy of supercoiled, circular, and double-stranded molecule of approximately 5.2 kb, associated with cellular histone proteins H2A, H2B, H3, and H4 and packaged into chromatin resembling cellular genomes (minichromosomes) [1, 3, 4]. The viral genome has a bipartite organization and contains two regions of about the same size, known as early and late transcription units, transcribed in opposite directions starting from a common hypervariable noncoding control region (NCCR), containing the origin of DNA replication (ori), the TATA box, cellular transcription factors binding sites, and bidirectional promoters and enhancers for the transcription of early and late genes. Starting from the NCCR, early transcription proceeds in a counterclockwise direction, while late transcription proceeds clockwise on the opposite strand of the DNA [5]. 2 Clinical and Developmental Immunology lytically infects oligodendrocytes, causing the demyelinating disease, known as PML [9–11]. VP1 T′165 2. Progressive Multifocal Leukoencephalopathy T′136 T′135 VP2 JCV VP3 t T′ AGNO T Late NCCR Early Figure 1: Schematic representation of the JCV genome organization. The circular, double-stranded DNA genome is ∼5.2 kb in size and is divided into the early coding region and the late coding region, transcribed in opposite directions from a common noncoding control region (NCCR). Early genes include large T antigen (T-Ag), small t antigen (t-Ag), T󸀠 135, T󸀠 136, and T󸀠 165. Late genes include VP1, VP2, VP3, and agnoprotein. The early region spans 2.4 kb and encodes the alternatively spliced transforming proteins, large tumor antigen (TAg) and small tumor antigen (t-Ag), which are involved in the viral replication and in promoting transformation of cells in culture and oncogenesis in vivo [5]. The late coding region spans 2.3 kb and encodes the capsid proteins VP1, VP2, and VP3 by alternative splicing of a common mRNA derived from the same primary late transcript and a small regulatory protein, known as agnoprotein, whose function in the virus life cycle is not completely clear [5] (Figure 1). JCV does not infect any species other than humans and its ability to infect human cells may be restricted at the level of viral early gene transcription and DNA replication, with the T-Ag interacting specifically with the human DNA polymerase [6]. JCV has a tropism for replication in human glial cells, kidney epithelial cells, and, with a less efficiency, in B lymphocytes, and the restricted CNS tropism is confirmed by both experimental animals and in vitro analysis [6, 7]. The transmission of JCV is not fully understood. JCVspecific antibodies are detected in approximately 70% of adults [8] and the primary infection occurs in early childhood, usually in an asymptomatic way and results in a primary viremia. Afterwards, the virus produces a persistent latent infection in the kidney and is shed into the urine. In the context of an immunosuppressive condition, such as AIDS and transplantation, JCV disseminates to the CNS and PML is a rare demyelinating disease characterized by the lytic infection of glial cells and is often fatal. The disease occurs almost exclusively in patients with severe immunodeficiency; consequently, the incidence of PML has increased dramatically, following the spread of HIV/AIDS. Nowadays, HIV infection is still the most frequent setting for PML, ∼80% of the cases, followed by hematologic malignancies (∼8%), solid cancers (∼3%), organ transplantation, and autoimmune diseases treated with immunomodulators [12]. The classic form of PML is progressive and multifocal and involves the white matter. The main symptoms of the disease are motor deficits, altered consciousness, gait ataxia, and visual disturbances [13, 14]. Atypical pre (...truncated)