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Journal of Neuroimmune Pharmacology

, Volume 12, Issue 2, pp 233–248 | Cite as

HIV-1 Viral Protein R Activates NLRP3 Inflammasome in Microglia: implications for HIV-1 Associated Neuroinflammation

  • Manmeet K. Mamik
  • Elizabeth Hui
  • William G. Branton
  • Brienne A. McKenzie
  • Jesse Chisholm
  • Eric A. Cohen
  • Christopher Power
ORIGINAL ARTICLE

Abstract

Human Immunodeficiency virus (HIV) enters the brain soon after seroconversion and induces chronic neuroinflammation by infecting and activating brain macrophages. Inflammasomes are cytosolic protein complexes that mediate caspase-1 activation and ensuing cleavage and release of IL-1β and −18 by macrophages. Our group recently showed that HIV-1 infection of human microglia induced inflammasome activation in NLRP3-dependent manner. The HIV-1 viral protein R (Vpr) is an accessory protein that is released from HIV-infected cells, although its effects on neuroinflammation are undefined. Infection of human microglia with Vpr-deficient HIV-1 resulted in reduced caspase-1 activation and IL-1β production, compared to cells infected with a Vpr-encoding HIV-1 virus. Vpr was detected at low nanomolar concentrations in cerebrospinal fluid from HIV-infected patients and in supernatants from HIV-infected primary human microglia. Exposure of human macrophages to Vpr caused caspase-1 cleavage and IL-1β release with reduced cell viability, which was dependent on NLRP3 expression. Increased NLRP3, caspase-1, and IL-1β expression was evident in HIV-1 Vpr transgenic mice compared to wild-type littermates, following systemic immune stimulation. Treatment with the caspase-1 inhibitor, VX-765, suppressed NLRP3 expression with reduced IL-1β expression and associated neuroinflammation. Neurobehavioral deficits showed improvement in Vpr transgenic animals treated with VX-765. Thus, Vpr-induced NLRP3 inflammasome activation, which contributed to neuroinflammation and was abrogated by caspase-1 inhibition. This study provides a new therapeutic perspective for HIV-associated neuropsychiatric disease.

Keywords

HIV-1 Neuroinflammation Inflammasomes NLRP3 Viral protein R Interleukin-1 beta 

Notes

Acknowledgments

This work was supported by grants from the Canadian Institutes of Health Research (CP, EAC) and fellowships from the Alberta Innovates-Health Solutions (MM, EH) and Campus Alberta Neuroscience (MM). CP and EAC hold Canada Research Chairs (Tier 1) in Neurological Infection & Immunity and Human Retrovirology, respectively. The following reagent was obtained through the NIH AIDS Reagent Program, Division of AIDS, NIAID, NIH: pSVIII-92TH014.12 from Dr. Feng Gao and Dr. Beatrice Hahn.

Compliance with Ethical Standards

Competing Interests

The authors have no financial conflicts of interest.

Supplementary material

11481_2016_9708_MOESM1_ESM.pdf (187 kb)
ESM 1 (PDF 187 kb)
11481_2016_9708_MOESM2_ESM.doc (43 kb)
ESM 2 (DOC 43 kb)

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Copyright information

© Springer Science+Business Media New York 2016

Authors and Affiliations

  • Manmeet K. Mamik
    • 1
  • Elizabeth Hui
    • 1
  • William G. Branton
    • 1
  • Brienne A. McKenzie
    • 1
  • Jesse Chisholm
    • 1
  • Eric A. Cohen
    • 2
  • Christopher Power
    • 1
  1. 1.Department of MedicineUniversity of AlbertaEdmontonCanada
  2. 2.Institut de recherches cliniques de Montréal (IRCM) and Department of Microbiology, Infectiology and ImmunologyUniversité de MontréalMontrealCanada

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