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Implications for Virus Reactivation After Immunosuppression in Transplant Patients and the Occurrence of PML Disease

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Implications for Virus Reactivation After Immunosuppression in Transplant Patients and the Occurrence of PML Disease Review JC Polyomavirus and Transplantation: Implications for Virus Reactivation after Immunosuppression in Transplant Patients and the Occurrence of PML Disease James E. K. Hildreth 1,2,3 and Donald J. Alcendor 1,3,* 1 Center for AIDS Health Disparities Research, Department of Microbiology and Immunology, School of Medicine, Meharry Medical College, 1005 Dr. D.B. Todd Jr. Blvd., Nashville, TN 37208, USA; [email protected] 2 Department of Internal Medicine, School of Medicine, Meharry Medical College, 1005 Dr. D.B. Todd Jr. Blvd., Nashville, TN 37208, USA 3 Center for AIDS Health Disparities Research, Immunology, and Physiology, Department of Microbiology, School of Medicine, Meharry Medical College, 1005 Dr. D.B. Todd Jr. Blvd., Nashville, TN 37208, USA * Correspondence: [email protected] Abstract: The JC polyomavirus (JCPyV/JCV) is a member of the Polyomaviridae family and is ubiqui- tious in the general population, infecting 50–80% of individuals globally. A primary infection with JCV usally results in an asymptomatic, persistent infection that establishes latency in the renourinary tract. Reactivation from latency via iatrogenic immununosuppression for allograft transplantation may result in organ pathology and a potential life-threatening neuropathological disease in the form of progressive multifocal leukoencephalopathy (PML). Currently, no treatment exists for PML, a rare complication that occurs after transplantation, with an incidence of 1.24 per 1000 persons a year among solid organ transplant patients. PML is also observed in HIV patients who are immununosup- Citation: Hildreth, J.E.K.; Alcendor, pressed and are not receiving antiretroviral therapy, as well as individuals treated with biologics to D.J. JC Polyomavirus and Transplantation: Implications for suppress chronic inflammatory responses due to multiple sclerosis, Crohn’s disease, non-Hodgkin’s Virus Reactivation after lymphoma, rheumatoid arthritis, and other autoimmune-mediated hematological disorders. Here, Immunosuppression in Transplant we describe the proposed mechanisms of JCV reactivation as it relates to iatrogenic immunosuppres- Patients and the Occurrence of PML sion for graft survival and the treatment of proinflammatory disease, such as biologics, proposed Disease. Transplantology 2021, 2, trafficking of JCV from the renourinary tract, JCV central nervous system dissemination and the 37–48. https://doi.org/10.3390/ pathology of PML in immunosuppressed patients, and potential novel therapeutics for PML disease. transplantology2010004 Keywords: JC polyomavirus; transplantation; progressive multifocal leukoencephalopathy; immuno- Academic Editor: Nassim Kamar suppression; neuropathology Received: 15 December 2020 Accepted: 29 January 2021 Published: 2 February 2021 1. Introduction Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in The JC polyomavirus (JCPyV/JCV) is a member of the Polyomaviridae family, genus published maps and institutional affil- Orthopolyomavirus, which also includes the BK polyomavirus (BKPyV/BKV) [1–3]. Both iations. viruses were isolated from patients with the initial JC and BK polyomaviruses, respec- tively [1,2]. JCV is thought to be transmitted by inhylation and infects 50–80% of the global population [4,5], with 10–30% of the world population shedding JCV in their urine [6]. JCV produces an asymptomatic, persistent infection primarily in the renourinary tract, reactivating only when the immune system is compromised. The reactivation of latent Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland. JCV in the brain of immune-compromised individuals may result in a lytic infection of This article is an open access article oligodendrocytes, glial cells, and astrocytes [7–11]. The demyelination of oligodendrocytes distributed under the terms and induced by JCV lytic replication may lead to progressive multifocal leukoencephalopathy conditions of the Creative Commons (PML). PML is a frequently fatal demyelinating infectious disease of the brain caused Attribution (CC BY) license (https:// by neuropathogenic prototypes of JCV and is accompanied by progressive neurological creativecommons.org/licenses/by/ deficits and death [11–15]. The spectrum of neurological presentations includes ataxia, 4.0/). hemiparesis, hemianopia, cognitive impairment, limb ataxia, gait disorder, and aphasia. Transplantology 2021, 2, 37–48. https://doi.org/10.3390/transplantology2010004 https://www.mdpi.com/journal/transplantology Transplantology 2021, 2 38 The commonly involved areas include the subcortical white matter, periventricular areas, and cerebellar peduncles. PML is rare, with an incidence of <0.3/100,000 persons a year among the general population [16]. However, the incidence of PML HIV/AIDS patients without antiretroviral therapy is 2.4 per 1000 persons a year [17]. PML occurs in 3–5% of HIV-infected individuals with an uncontrolled disease, but HIV therapy has been shown to improve clinical outcomes [6,10,11,18]. This is a significantly higher incidence when compared to patients with other means of immunomodulation therapy. The clinical presen- tations of PML disease include motor weakness, speech abnormalities, cognitive deficits, headache, visual fields deficits, ataxia, aphasia, cranial nerve deficits, and seizures [8,10,19]. Currently, no specific treatment exists for JCV-induced PML. This represents an urgent unmet medical need for efficacious therapeutics for JCV-induced PML in immunocompro- mised patients. In addition, no suitable animal model for PML exists due to the failure of JCV to productively replicate in nonhuman hosts cells [20,21]. Here, we examine the role of iatrogenic immunosuppression on JCV reaction and the neuropathology that may result post-reactivation. 2. JCPyV Biology JCV, along with BKV, identified in 1971, were the first two polyomaviruses associated with human, but not oncogenic, disease [2,3]. To date, 13 different polyomaviruses exist that may infect humans, and this number likely will rise due to novel methodologies used in virus discovery [22]. Five out of the 13 human polyomaviruses have been associated with clinical disease, including JCV, BKV, Trichodysplasia spinulosa polyomavirus, human polyomavirus 7, and Merkel cell polyomavirus [22]. JCV is a small nonenveloped, double- stranded, circular DNA virus with a five-kilobase genome associated with cellular histones, forming a viral mini-chromosome that replicates in the nucleus of permissive cells. Erickson et al. showed that the JCV recruits and modulates the host DNA damage response to replicate its genome [23]. JCV encodes six proteins, the large T and small t antigens, which have oncogenic properties, three capsid proteins (VP1–3), and the agnoprotein [24]. Currently, it is unknown whether the transmissible form of the virus is archetypal (found in the kidney, urine, and sewage, such as the CY strain of JCV); prototypical (found in the brain and is associated with PML, such as the Mad-1 strain of JCV); or both. These two types of JCV viruses differ only within their noncoding regulatory region (NCRR). The prototypical JCV-PML types isolated from the cerebrospinal fluid (CSF) and brain tissues from PML patients have rearrangements, including duplications, tandem repeats, and insertions and deletions in the NCRR region. Evidence of JCV persistence has been found in renal tissue, bone marrow, and brain tissue. This state of persistence appears as episomal circular DNA that is nonreplicating, with no viral gene transcription. Evidence of genomic DNA in normal brain tissue has been observed [25]. The asymptomatic shedding of JCV occurs in the adult human population at a level of 50,000 copies/mL of urine. It has been demonstrated by Coleman et al. that pregnant women in their second and third trimesters may shed JCV asymptomatically at a rate of 3.2% [26]. The seropositivity rates for JCV are found in the range from 39% to 81% and to steadily rise as an individual reaches adulthood, having more sustained viral titers when compared to BKV [5,27]. Primary infections are thought to occur in childhood via the upper respiratory tract through inhalation and, also, via the gastrointestinal route due to contaminated food or water (Figure1). These findings are supported by the presence of JCV in the tonsils and intestinal cells, respectively [28–30]. In addition, JCV is known to infect B cells in the peripheral circulation, adding to the complexity of viral transmission (Figure1). JCV infection is endemic and ubiquitous, and transmission occurs in childhood by the feco-oral, urino- oral, and respiratory routes. The virus will remain latent in the bone marrow, kidneys, tonsils, lymphoid tissues, and/or the brain throughout the life of an infected individual (Figure1 ). Over time, if an individual becomes immunocompromised, JCV may reactivate from latency and cause a life-threatening clinical disease, most notably in the form of PML (Figure1). Transplantology 2021, 2, FOR PEER REVIEW 3 oral, and respiratory routes. The virus will remain latent in the bone marrow, kidneys, tonsils, lymphoid tissues, and/or the brain throughout the life of an infected individual (Figure 1). Over time, if an individual becomes immunocompromised, JCV may reactivate from latency and cause a life-threatening clinical disease, most notably in the form of PML (Figure 1). Transplantology 2021, 2 39 Figure 1. JC polyomavirusFigure (JCV) 1. infection JC polyomavirus and dissemination (JCV) infect fromion and environmental dissemination exposure from en tovironmental
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