Journal of NeuroVirology

, 17:382

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

Authors

    • Department of NeurologyJohns Hopkins University School of Medicine
  • Tanzeem Islam
    • Department of NeurologyJohns Hopkins University School of Medicine
  • Robert Adams
    • Department of NeurologyJohns Hopkins University School of Medicine
  • Sujata Nerle
    • Department of NeurologyJohns Hopkins University School of Medicine
  • Masiray Kamara
    • Department of NeurologyJohns Hopkins University School of Medicine
  • Caitlin Eger
    • Department of NeurologyJohns Hopkins University School of Medicine
  • Karen Marder
    • Department of Neurology, Psychiatry, Sergievsky Center and Taub Institute on Alzheimer’s Disease and the Aging Brain, New York Presbyterian HospitalColumbia University College of Physicians and Surgeons
  • Bruce Cohen
    • Department of NeurologyNorthwestern University Feinberg School of Medicine
  • Giovanni Schifitto
    • Department of Neurology, School of Medicine and DentistryUniversity of Rochester
  • Justin C. McArthur
    • Department of NeurologyJohns Hopkins University School of Medicine
  • Ned Sacktor
    • Department of NeurologyJohns Hopkins University School of Medicine
  • Carlos A. Pardo
    • Department of NeurologyJohns Hopkins University School of Medicine
Article

DOI: 10.1007/s13365-011-0035-4

Cite this article as:
Brown, A., Islam, T., Adams, R. et al. J. Neurovirol. (2011) 17: 382. doi:10.1007/s13365-011-0035-4

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.

Keywords

HIV-associated neurocognitive disorderCD44Nef

Supplementary material

13365_2011_35_MOESM1_ESM.doc (48 kb)
Table 2Clinical Characteristics of Brain Tissue Samples (DOC 47 kb)

Copyright information

© Journal of NeuroVirology, Inc. 2011