title: Osteopontin enhances HIV replication and is increased in the brain and cerebrospinal fluid of HIV-infected individuals.
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.
authors.affiliation: Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21287-7131, USA. abrown76@jhmi.edu
authors.forename: Amanda
authors.initials: A
authors.lastname: Brown
authors.forename: Tanzeem
authors.initials: T
authors.lastname: Islam
authors.forename: Robert
authors.initials: R
authors.lastname: Adams
authors.forename: Sujata
authors.initials: S
authors.lastname: Nerle
authors.forename: Masiray
authors.initials: M
authors.lastname: Kamara
authors.forename: Caitlin
authors.initials: C
authors.lastname: Eger
authors.forename: Karen
authors.initials: K
authors.lastname: Marder
authors.forename: Bruce
authors.initials: B
authors.lastname: Cohen
authors.forename: Giovanni
authors.initials: G
authors.lastname: Schifitto
authors.forename: Justin C
authors.initials: JC
authors.lastname: McArthur
authors.forename: Ned
authors.initials: N
authors.lastname: Sacktor
authors.forename: Carlos A
authors.initials: CA
authors.lastname: Pardo
mesh_terms: D015526:AIDS Dementia Complex / Q000097:blood / Q000134:cerebrospinal fluid / Q000209:etiology / Q000235:genetics* / Q000473:pathology / Q000821:virology; D015415:Biomarkers / Q000097:blood / Q000134:cerebrospinal fluid; D001921:Brain / Q000473:pathology / Q000821:virology*; D002478:Cells, Cultured; D015870:Gene Expression / Q000187:drug effects; D020869:Gene Expression Profiling; D055785:Gene Knockdown Techniques; D015658:HIV Infections / Q000097:blood / Q000134:cerebrospinal fluid / Q000150:complications / Q000235:genetics* / Q000473:pathology / Q000821:virology; D015497:HIV-1 / Q000502:physiology*; D006801:Humans; D020672:I-kappa B Proteins / Q000494:pharmacology; D007249:Inflammation / Q000097:blood / Q000134:cerebrospinal fluid / Q000209:etiology / Q000235:genetics* / Q000473:pathology / Q000821:virology; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D009154:Mutation; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D053495:Osteopontin / Q000235:genetics / Q000378:metabolism; D016133:Polymerase Chain Reaction; D061251:Primary Cell Culture; D034741:RNA, Small Interfering / Q000494:pharmacology; D012720:Severity of Illness Index; D015398:Signal Transduction / Q000187:drug effects; D014779:Virus Replication / Q000187:drug effects / Q000502:physiology
chemical_list: D015415:Biomarkers; D020672:I-kappa B Proteins; D016328:NF-kappa B; C000606204:NFKBIA protein, human; D034741:RNA, Small Interfering; C506895:SPP1 protein, human; D053495:Osteopontin; D000072000:NF-KappaB Inhibitor alpha