Osteopontin enhances HIV replication and is increased in the brain and cerebrospinal fluid of HIV-infected individuals
Title | Osteopontin enhances HIV replication and is increased in the brain and cerebrospinal fluid of HIV-infected individuals |
Publication Type | Journal Article |
Year of Publication | 2011 |
Authors | Brown, A, Islam, T, Adams, R, Nerle, S, Kamara, M, Eger, C, Marder, K, Cohen, BA, Schifitto, G, McArthur, JC, Sacktor, N, Pardo, C |
Journal | Journal of NeuroVirology |
Volume | 17 |
Issue | 4 |
Pagination | 382-392 |
Date Published | 08/2011 |
Keywords | CD44, External, HIV-associated neurocognitive disorder, Nef |
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. |
URL | http://www.ncbi.nlm.nih.gov/pubmed/21556958 |
DOI | 10.1007/s13365-011-0035-4 |