Reversing interferon-alpha neurotoxicity in a HIV-associated neurocognitive disorder mouse model

Rajeth Koneru, Heather Bimonte-Nelson, Vincent Ciavatta, Woldeab Haile, Kate Elmore, Jennifer Ward, Leonard Maroun, William R. Tyor

Research output: Contribution to journalArticlepeer-review

6 Scopus citations

Abstract

Objective: Increased brain interferon-alpha (IFN) is associated with neurodegenerative disorders, including HIV-associated neurocognitive disorders (HAND). HAND occurs in approximately 50% of individuals with HIV despite combined antiretroviral therapy (cART). Therefore, adjunctive therapies must be developed that prevent progression of mild forms of HAND to HIV-associated dementia. Increased IFN in the CNS has been associated with HAND in patients and in a HAND mouse model. Design and methods: B18R binds IFN and ameliorates HAND mouse brain histopathology (HIV encephalitis). The HAND model was used to determine if B18R with cART is superior to cART. Behavioral testing [Object recognition Test (ORT)] was used to show that B18R can reverse behavioral deficits. Rat neuronal cultures were used to investigate mechanisms of IFN neurotoxicity. Results: Mouse brain immunohistochemistry and densitometry suggests that B18R with a common cART regimen improve histopathological markers better than cART alone. B18R reverses ORT behavioral abnormalities in HAND mice. IFN-treated rat neurons show decreases in PSD-95, suggesting that dendritic spine architecture is disrupted. Decreases in Arf1, a GTP-binding protein, and AMPA receptors on the surface of rat neurons exposed to IFN suggest the mechanism of IFN neurotoxicity may relate to decreased Arf1 resulting in destabilization of dendritic spines, decreased PSD-95 expression, and internalization of AMPA receptors. Conclusion: B18R reversal of HAND in the mouse model is further evidence that the treatment of IFN in individuals with HAND could be a viable adjunctive treatment. Investigating pathways of IFN neurotoxicity may lead to more specific treatments.

Original languageEnglish (US)
Pages (from-to)1403-1411
Number of pages9
JournalAIDS
Volume32
Issue number11
DOIs
StatePublished - Jul 17 2018

Keywords

  • HIV-associated neurocognitive disorders
  • dendrites
  • interferon-alpha
  • mouse model
  • rat neuronal cultures
  • treatment

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology
  • Infectious Diseases

Fingerprint Dive into the research topics of 'Reversing interferon-alpha neurotoxicity in a HIV-associated neurocognitive disorder mouse model'. Together they form a unique fingerprint.

Cite this