Progressive multifocal leukoencephalopathy: Lessons from AIDS and natalizumab
Department of Neurology, University of Kentucky College of Medicine, Lexington, 40536, USA. Neurological Research
(Impact Factor: 1.44).
05/2006; 28(3):299-305. DOI: 10.1179/016164106X98198
The dramatic increase in the incidence of progressive multifocal leukoencephalopathy (PML) that occurred as a consequence of the AIDS pandemic and the recent association of PML with the administration of natalizumab, a monoclonal antibody to alpha4 integrin that blocks inflammatory cell entry into the brain, has stimulated a great deal of interest in this previously obscure viral demyelinating disease. The etiology of this disorder is JC virus (JCV), a polyoma virus, observed in 80% of the population worldwide. Seroepidemiological studies indicate that infection with this virus typically occurs before the age of 20 years. No primary illness owing to JCV infection has been recognized and the means of spread from person to person remains obscure. Following infection, the virus becomes latent in bone marrow, spleen, tonsils and other tissues. Periodically the virus reactivates during which time it can be demonstrated in circulating peripheral lymphocytes. The latter is significantly more commonly observed in immunosuppressed populations than that in normal subjects. Despite the large pool of people infected with JCV, PML remains a relatively rare disease. It is seldom observed in the absence of an underlying predisposing illness, typically one that results in impaired cellular immunity. A variety of factors are likely responsible for the unique increase in frequency of PML in HIV infection relative to other underling immunosuppressive disorders. Preliminary data suggests that natalizumab appears to distinctively predispose recipients to PML relative to other infectious complications. Studies in these populations will be invaluable in understanding the mechanisms of disease pathogenesis.
Available from: Constantine Bitsaktsis
- "JCV is primarily associated with progressive multifocal leukoencephalopathy (PML), a debilitating opportunistic infection that affects AIDS patients, and in rare cases occurs in individuals undergoing immunosuppressive therapy. PML manifests as dementia, confusion, and vision impairment resulting from demyelination in the CNS (Bellizzi et al., 2012; Berger and Houff, 2006; Van Assche et al., 2005). BKV has been associated with acute interstitial nephritis and hemorrhagic cystitis in stem cell transplant recipients (Dalianis and Hirsch, 2013). "
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ABSTRACT: Infection with various human polyomaviruses (HPyVs) is prevalent, with rates as high as 80 % within the general population. Primary infection occurs during childhood through respiratory or urino-oral transmission. While the majority of individuals exhibit asymptomatic latent infection, those immunocompromised persons are at risk for viral reactivation and disease progression resulting in conditions such as progressive multifocal leukoencephalopathy (PML), trichodysplasia spinulosa, Merkel cell carcinoma, and polyomavirus associated nephropathy. Individuals with altered immune systems due to HIV, organ transplantation, lymphoproliferative diseases, and monoclonal antibody therapy are particularly susceptible to reactivation of various HPyVs. While the specific factors that induce lytic infection have yet to be defined, it is evident that dysfunctional host cellular immune responses allow active infection to occur. Immunosuppressant conditions, such as in chronic alcohol abuse, may serve as added risk factors for reactivation of HPyVs. Since the human HPyV family is rapidly expanding, continuing studies are needed to characterize the role that known and newly discovered HPyVs play in human disease.
Journal of NeuroVirology 01/2014; 20(1). DOI:10.1007/s13365-014-0234-x · 2.60 Impact Factor
Available from: Lucia Nencioni
- "CD8+ T cell responses specific to JCV are important to control JCV [43, 48, 49], and, during chronic viral infections, CD4+ T cells are required to maintain a CD8+ T cell response . Moreover increased circulation of B cells, which may favor JCV crossing of the BBB, has also been observed during HIV infection . Thus, HIV infection seems to promote an immunological state that favors the onset of PML. "
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ABSTRACT: John Cunningham virus (JCV) is a member of the Polyomaviridae family. It was first isolated from the brain of a patient with Hodgkin disease in 1971, and since then the etiological agent of the progressive multifocal leukoencephalopathy (PML) was considered. Until the human immunodeficiency virus (HIV) pandemic, PML was rare: in fact HIV-induced immunodeficiency is the most common predisposing factor accounting for 85% of all instances of PML. This data led to intense research on JCV infection and resulted in better understanding of epidemiology and clinic-pathologic spectrum. Recently, cases of PML have been observed after the introduction of monoclonal antibodies, such as natalizumab, rituximab, efalizumab, and infliximab, in the treatment of autoimmune disease, underlining the important role of host immunity in PML pathogenesis. In this review current understanding of the JCV infection and the new findings relating to the pathogenesis of PML has been comprehensively revised, focusing our attention on the interaction between the cellular and viral molecular pathways implicated in the JCV infection and the modulating role of host immune surveillance in the viral reactivation from a latent state.
Clinical and Developmental Immunology 04/2013; 2013(7712):839719. DOI:10.1155/2013/839719 · 2.93 Impact Factor
Available from: Patric Lundberg
- "Under certain conditions, which include immunosuppression, JCV can infect oligodendroglia in the brain causing the debilitating demyelinating disease, progressive multifocal leukoencephalopathy (PML)       . PML is a significant fatal opportunistic infection in AIDS, affecting nearly 4% of patients, and it has emerged as a dire but rare consequence of treatment with several new immunosuppressive therapeutic agents    . The ability of JCV to infect many people and to undergo altered ability to infect different cell types of only a minority of these people may be a common characteristic of certain newly discovered polyomaviruses. "
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ABSTRACT: Polyomavirus JC (JCV) is the etiological agent of progressive multifocal leukoencephalopathy (PML), a demyelinating infection of oligodendrocytes in the brain. PML, a frequently fatal opportunistic infection in AIDS, has also emerged as a consequence of treatment with several new immunosuppressive therapeutic agents. Although nearly 80% of adults are seropositive, JCV attains an ability to infect glial cells in only a minority of people. Data suggest that JCV undergoes sequence alterations that accompany this ability, and these changes can be derived from an archetype strain by mutation, deletion, and duplication. While the introductory source and primary tissue reservoir of JCV remain unknown, lymphoid cells have been identified as potential intermediaries in progression of JCV to the brain. This review is focused on sequence changes in the noncoding control region (NCCR) of the virus. We propose an adaptive mechanism that involves a sequential series of DNA replication-driven NCCR recombination events involving stalled DNA replication forks at NCCR palindromic secondary structures. We shall describe how the NCCR sequence changes point to a model in which viral DNA replication drives NCCR recombination, allowing JCV adaptation to different cell types in its progression to neurovirulence.
Clinical and Developmental Immunology 04/2013; 2013(4):197807. DOI:10.1155/2013/197807 · 2.93 Impact Factor
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