# Mechanisms of Interferon-alpha Neurotoxicity

> **NIH VA I01** · VETERANS HEALTH ADMINISTRATION · 2020 · —

## Abstract

Worldwide there are over 35 million individuals living with HIV. As many as 50% of these HIV-infected
individuals will develop HIV associated neurocognitive disorders (HAND), despite combined antiretroviral
therapy (cART). Yet, since the advent of cART the incidence of HIV associated dementia, the most severe
form of HAND, has diminished and represents less than 5% of HAND in countries like the US where cART is
available. Therefore, mild forms of HAND, such as Asymptomatic Neurocognitive Impairment and Mild
Neurocognitive Disorder, now predominate. Eventually these mild forms of HAND lead to HIV associated
dementia and its severe consequences. In addition, because HIV-infected individuals are living longer, they are
susceptible to age related diseases like Alzheimer’s disease, which can exacerbate HAND. Consequently,
adjunctive therapies [to cART] must be developed. Interferon-alpha (IFNα) is elevated in the cerebrospinal fluid
of HAND patients and correlates with cognitive dysfunction. Studies, including both clinical and basic, have
established that IFNα is neurotoxic causing cognitive dysfunction and neuronal dendritic abnormalities. Our
investigations suggest that IFNα could be a target for adjunctive therapies for HAND.
 A model of HAND in SCID mice was developed and forms an important part of the translational
component of this proposal. This model demonstrates behavioral similarities to HAND in humans. The model
has been useful in studying pathogenesis and the development of novel treatments. Recent improvements
using object recognition testing before and after treatment enable us to determine reversal of behavioral
abnormalities by novel therapies. This aspect of the model is particularly important because it reflects mild
cognitive impairment in humans with HAND, the most common forms, and thus models conditions occurring in
human clinical trials. As a result, the HAND model represents a valuable tool for pre-clinical screening of novel
adjunctive therapies. Also, IFNα is elevated in brains of HAND mice and blocking IFNα in HAND mice is an
effective treatment that may prove effective in HAND patients. Nevertheless, neutralizing IFNα in humans may
not be ultimately practical due to potential side effects. Therefore, rat neuronal cultures are used to study the
mechanisms of IFNα neurotoxicity. By studying the mechanisms of IFNα neurotoxicity, novel approaches to
treatment of HAND, and perhaps other cognitive disorders, may be developed.
 Studies have shown that IFNα neurotoxicity is mediated through both the IFNα receptor (IFNAR) and
the NMDA receptor (NMDAR). Rat neurons exposed to IFNα exhibit decreases in dendritic length and
branching. Recent work demonstrates decreased PSD-95 puncta along dendrites, suggesting more specific
mechanisms of toxicity. Proteomics demonstrate decreases in Arf1, Cdc42, and β-catenin, which are critical
intracellular signaling proteins that are intimately involved in dendritic spine scaffolding. Arf1 decrease...

## Key facts

- **NIH application ID:** 9886071
- **Project number:** 5I01BX001506-06
- **Recipient organization:** VETERANS HEALTH ADMINISTRATION
- **Principal Investigator:** WILLIAM R TYOR
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2020
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2013-10-01 → 2023-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9886071

## Citation

> US National Institutes of Health, RePORTER application 9886071, Mechanisms of Interferon-alpha Neurotoxicity (5I01BX001506-06). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9886071. Licensed CC0.

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