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| Content Provider | Springer Nature Link |
|---|---|
| Author | Brown, Amanda Islam, Tanzeem Adams, Robert Nerle, Sujata Kamara, Masiray Eger, Caitlin Marder, Karen Cohen, Bruce Schifitto, Giovanni McArthur, Justin C. Sacktor, Ned Pardo, Carlos A. |
| Copyright Year | 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. |
| Starting Page | 382 |
| Ending Page | 392 |
| Page Count | 11 |
| File Format | |
| ISSN | 13550284 |
| Journal | Journal of NeuroVirology |
| Volume Number | 17 |
| Issue Number | 4 |
| e-ISSN | 15382443 |
| Language | English |
| Publisher | Springer US |
| Publisher Date | 2011-05-10 |
| Publisher Place | Boston |
| Access Restriction | One Nation One Subscription (ONOS) |
| Subject Keyword | HIV-associated neurocognitive disorder CD44 Nef Infectious Diseases Virology Immunology Neurosciences Neurology |
| Content Type | Text |
| Resource Type | Article |
| Subject | Neurology Virology Neurology (clinical) Cellular and Molecular Neuroscience |
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