HIV: How Protease Inhibitors May Lead to Neurocognitive Disorders

Studies have shown that HIV increases the risk of confusion and forgetfulness, but new research found that the virus is tied to more serious neurocognitive conditions.

A new study of antiretroviral medications in both tissue samples and lab animals identifies how some human immunodeficiency virus (HIV) treatments may produce neurocognitive disorders in long-term users.

Numerous prior studies have shown that HIV is associated with a greater risk of forgetfulness, confusion, behavioral changes, and declining motor skills. Some of that research has implicated antiretroviral medications as the cause of such problems.

Investigators hypothesized that antiretroviral medications were creating endoplasmic reticulum (ER) stress in the central nervous system, which led to chronic dysregulation of unfolded protein response and changed amyloid precursor protein (APP) processing.

Experiments conducted in vitro and in vivo models showed that the protease inhibitor class of antiretroviral medications did indeed induce neuronal damage and ER stress, which led to PKR-like ER kinase-dependent phosphorylation of the eukaryotic transition initiation factor 2α and enhanced translation of β-site APP cleaving enzyme-1 (BACE1).

In rodent neuroglial cultures and human APP-expressing Chinese hamster ovary cells, the protease inhibitors induced β-amyloid production, which indicated increased BACE1-mediated APP processing. In mice and SIV-infected macaques, moreover, antiretroviral medication resulted in neuronal damage and BACE1 up-regulation in the central nervous system.

Fortunately, the investigators also found during the in vitro studies that inhibiting the activity of BACE1, which is often associated with Alzheimer’s disease, protected against neuronal damage. This suggests that a drug designed to target this pathway would allow people with HIV to reduce their risk of neurocognitive decline without altering their treatment.

“Protease inhibitors are very effective antiviral therapies, but they do have inherent toxicities,” said senior study author Kelly Jordan-Sciutto, PhD, who chairs the Department of Pathology at the University of Pennsylvania’s School of Dental Medicine. “Our findings may cause us to rethink how we’re using these drugs and even consider developing an adjunctive therapy to reduce some of these negative effects.”

Previous research by the same team, along with research conducted largely out of Northwestern University, had shown that protease inhibitor use was associated with activation of stress-response pathways—including the unfolded-protein response, which causes a halt in protein translation and can lead to cellular damage or death.

It was not clear, however, whether this response stemmed primarily from the medications or from the disease they were treating. It was also unclear what molecules mediated the response.

This new study confirmed that protease inhibitors, rather than HIV, trigger the activation of stress-response pathways by comparing SIV—positive macaques that were treated with such medications with untreated controls. It found the treated animals expressed more APP and more BACE1 than untreated animals. It also showed that both ritonavir and saquinavir caused significant increases in BACE1 when administered to healthy mice.

“Putting this together with our earlier findings on oxidative stress, it appears that the drugs are triggering oxidative stress that is damaging proteins and inducing the unfolded protein response,” said co-author Cagla Akay Espinoza, MD. “The virus itself provides a stress, but the drugs are causing additional stress and damage to neurons, in part by BACE1 leading to downstream processing of amyloid precursor protein.”

The study, “HIV Protease Inhibitors Alter Amyloid Precursor Protein Processing via β-Site Amyloid Precursor Protein Cleaving Enzyme-1 Translational Up-Regulation," appeared in the American Journal of Pathology. Additional information comes from a University of Pennsylvania news release.

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