Progressive multifocal leukoencephalopathy (PML) is a potentially fatal demyelinating disease of the central nervous system (CNS) caused by reactivation of latent JC polyomavirus (JCPyV), a highly neurotropic human polyomavirus, which initiates disease by lytically infecting oligodendrocytes. Approximately 50-70% of the general population has been exposed to JCPyV; the infection is usually clinically inapparent and the virus remains latent. PML can occur in immunosuppressed/immunocompromised individuals following organ transplantation or chemotherapy as well as in about 3-5% of acquired immunodeficiency syndrome cases. Therefore, PML usually follows marked immunosuppression. However, the recent development of immunomodulatory therapies for the treatment of various autoimmune diseases has led to the existence of therapy-induced PML. Examples of immunomodulatory therapies resulting in PML include: natalizumab (Tysabri(r)), a humanized monoclonal antibody (mAb) against the integrin ?4?1 for the treatment of relapsing- remitting multiple sclerosis and Crohn's disease; rituximab, a chimeric mAb against CD20, for the treatment of rheumatoid arthritis; and efalizumab, a humanized neutralizing mAb against the integrin aL?2 for the treatment of psoriasis. This demonstrates that the development of PML due to polyomavirus reactivation should be a major concern in the development of new immunomodulatory therapeutics for autoimmune diseases. Murine pneumotropic virus (MPtV), formerly known as Kilham polyomavirus, is a member of the Polyomavirus genus that infects mice. This virus is distinct from mouse polyomavirus (MPyV) and is a separate species. Others have shown that infection of weanling mice leads to inapparent clinical disease; however, the tissue distribution of MPtV is similar to what is observed in humans infected with human polyomavirus. After about six months, infectious MPtV was not detectable in any tissues. However, weekly injections of cyclophosphamide, an immunosuppressive agent, into latently infected mice resulted in detectable virus in various organs as soon as one week post-cyclophosphamide treatment. Virus increased in amount until day 14 post-immunosuppressive treatment. By immunofluorescence staining and virus isolation, virus was detected in lung, liver, spleen, kidney, intestine and CNS. Virus has been found in vascular endothelial cells in the CNS and, following immunosuppression, in renal tubular epithelial cells. This is similar to the human polyomavirus JCPyV where virus reactivation results in the detection of virus in tubular epithelium. In vitro studies have shown that MPtV can also persist in murine glial cells, suggesting a possible site of viral latency. We propose to develop a novel viral latency model using MPtV infection of mice. We will explore whether this model can be a viable and potentially useful reagent to test immunomodulatory therapies where polyomavirus reactivation in the CNS is a problem. Currently there is no good model that can be used to predict how immunomodulatory therapies lead to human polyomavirus reactivation in the CNS.

Public Health Relevance

We are proposing to develop a novel viral latency model to investigate virus reactivation using polyomavirus (murine pneumotropic virus) infection of mice. The time course of viral latency and the location of latent virus will be characterized and the ability to reactivate virus through immunosuppressive and immunomodulatory treatments will be explored. If successful, this could be a useful model for testing potential therapies or treatments for autoimmune diseases where polyomavirus reactivation could be of major concern.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Small Research Grants (R03)
Project #
Application #
Study Section
Clinical Neuroimmunology and Brain Tumors Study Section (CNBT)
Program Officer
Wong, May
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Utah
Schools of Medicine
Salt Lake City
United States
Zip Code