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

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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.

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Acknowledgments

We thank the Margaret Q. Landenberger Foundation, the Campbell Foundation, and the Cooke Family Foundation for funding this work. We also thank Hao Zhang from the Flow Cytometry Core at the Johns Hopkins School of Public Health and Amy Kosel, Liping Guo, Peter Dziedzic, and Jason Creighton for technical assistance. The NEAD cohort was supported through NS44807 (JCM) and the data analysis and statistical review was supported through 1P30MH075673 (JCM). We thank The National NeuroAIDS Tissue Consortium supported through N01MH32002 for providing the brain tissue samples.

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Authors and Affiliations

  1. Department of Neurology, Johns Hopkins University School of Medicine, 600 North Wolfe Street/Meyer 6-181, Baltimore, MD, 21287-7131, USA

    Amanda Brown, Tanzeem Islam, Robert Adams, Sujata Nerle, Masiray Kamara, Caitlin Eger, Justin C. McArthur, Ned Sacktor & Carlos A. Pardo

  2. Department of Neurology, Psychiatry, Sergievsky Center and Taub Institute on Alzheimer’s Disease and the Aging Brain, New York Presbyterian Hospital, Columbia University College of Physicians and Surgeons, New York, NY, 10032, USA

    Karen Marder

  3. Department of Neurology, Northwestern University Feinberg School of Medicine, 710 North Lake Shore Drive, Abbott Hall 1121, Chicago, IL, 60611, USA

    Bruce Cohen

  4. Department of Neurology, School of Medicine and Dentistry, University of Rochester, 601 Elmwood Ave, Box’673, Rochester, NY, 14642, USA

    Giovanni Schifitto

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  1. Amanda Brown
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  2. Tanzeem Islam
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Correspondence to Amanda Brown.

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Table 2

Clinical Characteristics of Brain Tissue Samples (DOC 47 kb)

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Brown, A., Islam, T., Adams, R. et al. Osteopontin enhances HIV replication and is increased in the brain and cerebrospinal fluid of HIV-infected individuals. J. Neurovirol. 17, 382–392 (2011). https://doi.org/10.1007/s13365-011-0035-4

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