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Human polyomavirus JC reactivation and pathogenetic mechanisms of progressive multifocal leukoencephalopathy and cancer in the era of monoclonal antibody therapies

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Abstract

Progressive multifocal leukoencephalopathy (PML) is a demyelinating disease of the central nervous system caused by the neurotropic human polyomavirus JC (JCV) lytic infection of oligodendrocytes. PML was first described as a complication of lymphoproliferative disorders more than 50 years ago and emerged as a major complication of human immunodeficiency virus (HIV) infection in the 1980s. Despite the ubiquity of this virus, PML is rare and always seen in association with underlying immunosuppressive condition, such as HIV infection, autoimmune diseases, cancer, and organ transplantation. JCV remains quiescent in the kidneys, where it displays a stable archetypal non-coding control region (NCCR). Conversely, rearranged JCV NCCR, including tandem repeat patterns found in the brain of PML patients, have been associated with neurovirulence. The specific site and mechanism of JCV NCCR transformation is unknown. According to one model, during the course of immunosuppression, JCV departs from its latent state and after entering the brain, productively infects and destroys oligodendrocytes. Although the majority of PML cases occur in severely immunesuppressed individuals, PML has been increasingly diagnosed in patients treated with biological therapies such as monoclonal antibodies (mAbs) that modulate immune system functions: in fact, CD4+ and CD8+ T lymphopenia, resulting from this immunomodulatory therapy, are the primary risk factor. Furthermore, JCV reactivation in nonpermissive cells after treatment with mAbs, such as intestinal epithelial cells in Crohn’s disease patients, in association with other host tumor-inducing factors, could provide valid information on the role of JCV in several malignancies, such as colorectal cancer.

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Acknowledgments

This work was supported by MIUR grant.

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Authors and Affiliations

  1. Department of Health Sciences and Infectious Diseases, Sapienza University, P.le Aldo Moro, 5, 00185, Rome, Italy

    A. Bellizzi, E. Anzivino, D. M. Rodìo, F. Chiarini & V. Pietropaolo

  2. Department of Immunology and Allergology, Dermatology Institute (Istituto Dermopatico dell’Immacolata, IDI IRCSS), Rome, Italy

    C. Nardis

  3. Department of Obstetrics and Gynaecology Sciences & Urology Sciences, Sapienza University, Rome, Italy

    E. Anzivino

  4. National Institute for Infectious Diseases “Lazzaro Spallanzani”, Rome, Italy

    D. Fioriti

  5. Oncology and Genetics Doctoral School, University of Siena, Siena, Italy

    M. Mischitelli

  6. Sbarro Institute for Cancer Research and Molecular Medicine, Center for Biotechnology, College of Science and Technology, Temple University, Philadelphia, PA, USA

    V. Pietropaolo

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  1. A. Bellizzi
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Bellizzi, A., Nardis, C., Anzivino, E. et al. Human polyomavirus JC reactivation and pathogenetic mechanisms of progressive multifocal leukoencephalopathy and cancer in the era of monoclonal antibody therapies. J. Neurovirol. 18, 1–11 (2012). https://doi.org/10.1007/s13365-012-0080-7

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