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

Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21287-7131, USA.
Journal of NeuroVirology (Impact Factor: 2.6). 05/2011; 17(4):382-92. DOI: 10.1007/s13365-011-0035-4
Source: PubMed


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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Available from: Carlos A Pardo, Oct 04, 2015
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    • "Osteopontin is increased in the plasma and CSF of monkeys with SIV encephalitis and in HIV infected individuals [170] [171]. Interestingly, plasma osteopontin was increased only in individuals with cognitive impairment. "
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    ABSTRACT: HIV infected people are living longer due to the success of combined antiretroviral therapy (cART).However, greater than 40-70% of HIV infected individuals develop HIV associated neurocognitive disorders (HAND) that continues to be a major public health issue. While cART reduces peripheral virus, it does not limit the low level, chronic neuroinflammation that is ongoing during the neuropathogenesis of HIV. Monocyte transmigration across the blood brain barrier (BBB), specifically that of the mature CD14+CD16+ population that is highly susceptible to HIV infection, is critical to the establishment of HAND as these cells bring virus into the brain and mediate the neuroinflammation that persists, even if at low levels, despite antiretroviral therapy. CD14+CD16+ monocytes preferentially migrate into the CNS early during peripheral HIV infection in response to chemotactic signals, including those from CCL2 and CXCL12. Once within the brain, monocytes differentiate into macrophages and elaborate inflammatory mediators. Monocytes/macrophages constitute a viral reservoir within the CNS and these latently infected cells may perpetuate the neuropathogenesis of HIV. This review will discuss mechanisms that mediate transmigration of CD14+CD16+ monocytes across the BBB in the context of HIV infection, the contribution of these cells to the neuropathogenesis of HIV, and potential monocyte/macrophage biomarkers to identify HAND and monitor its progression.
    Current HIV Research 05/2014; DOI:10.2174/1570162X12666140526114526 · 1.76 Impact Factor
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    • "Recent studies have shown the correlation of serum OPN level with hepatic inflammation and fibrosis in association with alcohol intake [25]. Previously, several viruses such as murine polyoma virus middle T antigen, HBV X protein, and human immunodeficiency virus (HIV) have been shown to induce OPN which can lead to wound healing, cell migration, invasion and metastasis [26]–[28]. Recently, we have shown that HCV activates OPN via Ca2+ signaling and elevation of ROS [29]. "
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    ABSTRACT: Osteopontin (OPN) is a secreted phosphoprotein which has been linked to tumor progression and metastasis in a variety of cancers including hepatocellular carcinoma (HCC). Previous studies have shown that OPN is upregulated during liver injury and inflammation. However, the role of OPN in hepatitis C virus (HCV)-induced liver disease pathogenesis is not known. In this study, we determined the induction of OPN, and then investigated the effect of secreted forms of OPN in epithelial to mesenchymal transition (EMT), migration and invasion of hepatocytes. We show the induction of OPN mRNA and protein expression by HCV-infection. Our results also demonstrate the processing of precursor OPN (75 kDa) into 55 kDa, 42 kDa and 36 kDa forms of OPN in HCV-infected cells. Furthermore, we show the binding of secreted OPN to integrin αVβ3 and CD44 at the cell surface, leading to the activation of downstream cellular kinases such as focal adhesion kinase (FAK), Src, and Akt. Importantly, our results show the reduced expression of epithelial marker (E-cadherin) and induction of mesenchymal marker (N-cadherin) in HCV-infected cells. We also show the migration and invasion of HCV-infected cells using wound healing assay and matrigel coated Boyden chamber. In addition, we demonstrate the activation of above EMT markers, and the critical players involved in OPN-mediated cell signaling cascade using primary human hepatocytes infected with Japanese fulminant hepatitis (JFH)-1 HCV. Taken together, these studies suggest a potential role of OPN in inducing chronic liver disease and HCC associated with chronic HCV infection.
    PLoS ONE 01/2014; 9(1):e87464. DOI:10.1371/journal.pone.0087464 · 3.23 Impact Factor
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    • "Furthermore additional aspects of immunity, including B cells/immunoglobulin as well as the acute response are elevated. This study, the first of its kind in CNS infection by HIV or SIV, has led to a number of findings followed up in studies in humans as well as experimental animals, including the role of CD163+ monocytes/ macrophage/microglia (Roberts et al., 2004a; Kim et al., 2006; Borda et al., 2008), osteopontin (Burdo et al., 2007; Burdo et al., 2008; Marcondes et al., 2008; Brown et al., 2011), STAT1 (Potash et al., 2005; Chaudhuri et al., 2008), and the glycoprotein CHI3L1 (Bonneh-Barkay et al., 2008) in neuroAIDS. "
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    ABSTRACT: In the post-human genome project era, high throughput techniques to detect and computational algorithms to analyze differentially expressed genes have proven to be powerful tools for studying pathogenesis of neuroAIDS. Concurrently, discovery of non-coding RNAs and their role in development and disease has underscored the importance of examining the entire transcriptome instead of protein coding genes alone. Herein, we review the documented changes in brain RNA expression profiles in the non-human primate model of neuroAIDS (SIV infected monkeys) and compare the findings to those resulting from studies in post-mortem human samples of neuroAIDS. Differential expression of mRNAs involved in inflammation and immune response are a common finding in both monkey and human samples - even in HIV infected people on combination antiretroviral therapy, a shared set of genes is upregulated in the brains of both infected monkeys and humans: B2M, IFI44, IFIT3, MX1, STAT1. Additionally, alterations in ion channel encoding genes have been observed in the human studies. Brain miRNA profiling has also been performed, and up-regulation of two miRNAs originating from the same transcript, miR-142-3p and miR-142-5p, is common to human and monkey neuroAIDS studies. With increases in knowledge about the genome and advances in technology, unraveling alterations in the transcriptome in the SIV/monkey model will continue to enrich our knowledge about the effects of HIV on the brain.
    Journal of Neuroimmune Pharmacology 02/2012; 7(2):372-9. DOI:10.1007/s11481-012-9344-5 · 4.11 Impact Factor
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