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01-08-2011

Osteopontin enhances HIV replication and is increased in the brain and cerebrospinal fluid of HIV-infected individuals

Authors: Amanda Brown, Tanzeem Islam, Robert Adams, Sujata Nerle, Masiray Kamara, Caitlin Eger, Karen Marder, Bruce Cohen, Giovanni Schifitto, Justin C. McArthur, Ned Sacktor, Carlos A. Pardo

Published in: Journal of NeuroVirology | Issue 4/2011

Abstract

Despite effective and widely available suppressive anti-HIV therapy, the prevalence of mild neurocognitive dysfunction continues to increase. HIV-associated neurocognitive disorder (HAND) is a multifactorial disease with sustained central nervous system inflammation and immune activation as prominent features. Inflammatory macrophages, HIV-infected and uninfected, play a central role in the development of HIV dementia. There is a critical need to identify biomarkers and to better understand the molecular mechanisms leading to cognitive dysfunction in HAND. In this regard, we identified through a subtractive hybridization strategy osteopontin (OPN, SPP1, gene) an inflammatory marker, as an upregulated gene in HIV-infected primary human monocyte-derived macrophages. Knockdown of OPN in primary macrophages resulted in a threefold decrease in HIV-1 replication. Ectopic expression of OPN in the TZM-bl cell line significantly enhanced HIV infectivity and replication. A significant increase in the degradation of the NF-κB inhibitor, IκBα and an increase in the nuclear-to-cytoplasmic ratio of NF-κB were found in HIV-infected cells expressing OPN compared to controls. Moreover, mutation of the NF-κB binding domain in the HIV-LTR abrogated enhanced promoter activity stimulated by OPN. Interestingly, compared to cerebrospinal fluid from normal and multiple sclerosis controls, OPN levels were significantly higher in HIV-infected individuals both with and without neurocognitive disorder. OPN levels were highest in HIV-infected individuals with moderate to severe cognitive impairment. Moreover, OPN was significantly elevated in brain tissue from HIV-infected individuals with cognitive disorder versus those without impairment. Collectively, these data suggest that OPN stimulates HIV-1 replication and that high levels of OPN are present in the CNS compartment of HIV-infected individuals, reflecting ongoing inflammatory processes at this site despite anti-HIV therapy.

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Title: Osteopontin enhances HIV replication and is increased in the brain and cerebrospinal fluid of HIV-infected individuals
Authors: Amanda Brown
Tanzeem Islam
Robert Adams
Sujata Nerle
Masiray Kamara
Caitlin Eger
Karen Marder
Bruce Cohen
Giovanni Schifitto
Justin C. McArthur
Ned Sacktor
Carlos A. Pardo
Publication date: 01-08-2011
Publisher: Springer US
Published in: Journal of NeuroVirology / Issue 4/2011
Print ISSN: 1355-0284
Electronic ISSN: 1538-2443
DOI: https://doi.org/10.1007/s13365-011-0035-4

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Osteopontin enhances HIV replication and is increased in the brain and cerebrospinal fluid of HIV-infected individuals

Abstract

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Abstract

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