Immune reconstitution inflammatory syndrome and the central nervous system

Johnson, Tory P.; Nath, Avindra

doi:10.1097/wco.0b013e328346be57

Cited by 80 publications

(65 citation statements)

References 59 publications

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“…PML is a severely debilitating disease, and if left untreated, it is rapidly fatal. In addition, there is no antiviral drug targeting JCPyV which makes PML and PML-IRIS devastating (30). Therefore, it is crucial to investigate pharmacological approaches to prevent PML or to treat JCPyV infection.…”

Section: Discussionmentioning

confidence: 99%

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5-HT ₂ Receptors Facilitate JC Polyomavirus Entry

Assetta

Maginnis

Ahufinger

et al. 2013

J Virol

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Section: Discussionmentioning

confidence: 99%

“…There are no specific treatments for PML other than to restore immune function. However, immune restoration is associated with an immune reconstitution inflammatory syndrome (IRIS) that can be equally devastating (30). Most deaths in individuals taking natalizumab occur during IRIS (31,32).…”

mentioning

confidence: 99%

5-HT ₂ Receptors Facilitate JC Polyomavirus Entry

Assetta

Maginnis

Ahufinger

et al. 2013

J Virol

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“…The best treatment for PML is the restoration of the immune system, although even this is not ideal, since it can lead to IRIS. It is hence recommended that while interventions are being made to restore the immune function, such as initiation of antiretroviral agents in HIV-infected individuals and removal of the offending chemotherapeutic agent, the patients should be closely monitored for the development of IRIS and treated with steroids accordingly (219).…”

Section: Treatment Of Pml and Pml-irismentioning

confidence: 99%

Molecular Biology, Epidemiology, and Pathogenesis of Progressive Multifocal Leukoencephalopathy, the JC Virus-Induced Demyelinating Disease of the Human Brain

et al. 2012

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SUMMARY Progressive multifocal leukoencephalopathy (PML) is a debilitating and frequently fatal central nervous system (CNS) demyelinating disease caused by JC virus (JCV), for which there is currently no effective treatment. Lytic infection of oligodendrocytes in the brain leads to their eventual destruction and progressive demyelination, resulting in multiple foci of lesions in the white matter of the brain. Before the mid-1980s, PML was a relatively rare disease, reported to occur primarily in those with underlying neoplastic conditions affecting immune function and, more rarely, in allograft recipients receiving immunosuppressive drugs. However, with the onset of the AIDS pandemic, the incidence of PML has increased dramatically. Approximately 3 to 5% of HIV-infected individuals will develop PML, which is classified as an AIDS-defining illness. In addition, the recent advent of humanized monoclonal antibody therapy for the treatment of autoimmune inflammatory diseases such as multiple sclerosis (MS) and Crohn's disease has also led to an increased risk of PML as a side effect of immunotherapy. Thus, the study of JCV and the elucidation of the underlying causes of PML are important and active areas of research that may lead to new insights into immune function and host antiviral defense, as well as to potential new therapies.

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“…However, despite adequate viral control, chronic inflammation persists in ART-treated individuals with 20-35% developing a severe inflammation resulting in immune reconstitution inflammatory syndrome (IRIS) (1,2). IRIS is the most recognizable form of HIV-associated inflammation and, if it involves the central nervous system (CNS), it may result in death or permanent disability (3).…”

mentioning

confidence: 99%

Induction of IL-17 and nonclassical T-cell activation by HIV-Tat protein

Johnson

Patel

Johnson

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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Chronic immune activation is a major complication of antiretroviral therapy (ART) for HIV infection and can cause a devastating immune reconstitution inflammatory syndrome (IRIS) in the brain. The mechanism of T-cell activation in this population is not well understood. We found HIV-Tat protein and IL-17-expressing mononuclear cells in the brain of an individual with IRIS. Tat was also present in the CSF of individuals virologically controlled on ART. Hence we examined if Tat protein could directly activate T cells. Tat transcriptionally dysregulated 94 genes and induced secretion of 11 cytokines particularly activation of IL-17 signaling pathways supporting the development of a proinflammatory state. Tat increased IL-17 transcription and secretion in T cells. Tat entered the T cells rapidly by clathrin-mediated endocytosis and localized to both the cytoplasm and the nucleus. Tat activated T cells through a nonclassical pathway dependent upon vascular endothelial growth factor receptor-2 and downstream secondary signaling pathways but independent of the T-cell receptor. However, Tat stimulation of T cells did not induce T-cell proliferation but increased viral infectivity. This study demonstrates Tat's role as a virulence factor, by driving T-cell activation and contributing to IRIS pathophysiology. This supports the necessity of an anti-Tat therapy in conjunction with ART and identifies multiple targetable pathways to prevent Tat-mediated T-cell activation.

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Immune reconstitution inflammatory syndrome and the central nervous system

Cited by 80 publications

References 59 publications

5-HT ₂ Receptors Facilitate JC Polyomavirus Entry

5-HT ₂ Receptors Facilitate JC Polyomavirus Entry

Molecular Biology, Epidemiology, and Pathogenesis of Progressive Multifocal Leukoencephalopathy, the JC Virus-Induced Demyelinating Disease of the Human Brain

Induction of IL-17 and nonclassical T-cell activation by HIV-Tat protein

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Immune reconstitution inflammatory syndrome and the central nervous system

Cited by 80 publications

References 59 publications

5-HT 2 Receptors Facilitate JC Polyomavirus Entry

5-HT 2 Receptors Facilitate JC Polyomavirus Entry

Molecular Biology, Epidemiology, and Pathogenesis of Progressive Multifocal Leukoencephalopathy, the JC Virus-Induced Demyelinating Disease of the Human Brain

Induction of IL-17 and nonclassical T-cell activation by HIV-Tat protein

Contact Info

Product

Resources

About

5-HT ₂ Receptors Facilitate JC Polyomavirus Entry

5-HT ₂ Receptors Facilitate JC Polyomavirus Entry