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


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.


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



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

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ESM 1 (PDF 187 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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