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

Koneru, Rajetha; Bimonte-Nelson, Heatherb,c; Ciavatta, Vincenta; Haile, Woldeaba; Elmore, Katea; Ward, Jenniferd; Maroun, Leonardd; Tyor, William R.a,e

doi: 10.1097/QAD.0000000000001836
BASIC SCIENCE
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Objective: Increased brain interferon-alpha (IFNα) 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 IFNα in the CNS has been associated with HAND in patients and in a HAND mouse model.

Design and methods: B18R binds IFNα 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 IFNα 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. IFNα-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 IFNα suggest the mechanism of IFNα 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 IFNα in individuals with HAND could be a viable adjunctive treatment. Investigating pathways of IFNα neurotoxicity may lead to more specific treatments.

aAtlanta VA Medical Center, Decatur, Georgia

bArizona State University, Psychology Department, Tempe

cArizona Alzheimer's Consortium, Phoenix, Arizona

dMeiogen Biotechnology Corporation, Somerville, Massachusetts

eEmory University School of Medicine, Department of Neurology, Atlanta, Georgia, USA.

Correspondence to William R. Tyor, MD, Atlanta VA Medical Center, 1670 Clairmont Rd., Decatur, GA, 30033, USA. E-mail: wtyor@emory.edu

Received 21 December, 2017

Revised 30 March, 2018

Accepted 6 April, 2018

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