Popular HIV Drugs May Cause Neuronal Degeneration

Although antiretroviral drugs have made significant advancements in the treatment of HIV, even reducing mortality by 50%, evidence shows they may be associated with neuronal damage.

In a study published in the American Journal of Pathology, investigators pinpointed key players in neuronal damage. The findings suggest that certain protease inhibitors lead to peptide beta amyloid production, a process often associated with Alzheimer’s disease.

According to the study, protease inhibitor drugs jumpstart an increase in levels of an enzyme that cleaves the amyloid precursor protein (APP) to produce beta amyloid, which causes damage to the neurons.

“Protease inhibitors are very effective antiviral therapies, but they do have inherent toxicities,” said senior study author Kelly Jordan-Sciutto. “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.”

Most notably, the investigators found that inhibiting the enzyme BACE1 protected human and rodent brain cells. This suggests targeting the pathway with a new drug could reduce damage to neurons in patients on antiretroviral therapies.

Prior research shows that protease inhibitors can have toxic effects on the central nervous system. In one particular study, the investigators demonstrated how the drugs triggered the activation of stress-response pathways, including oxidative stress and unfolded-protein response (UPR).

UPR occurs when misfolded or modified proteins are sensed by the cell, causing a halt in protein translation. Normally, this is meant to protect a cell from aberrant proteins, but when chronically activated, it can lead to cellular damage or death, according to the study.

Despite these findings, it remained unclear whether UPR in HIV patients was primarily induced as a result of the virus or of the treatment, and what molecules mediated it. Furthermore, the investigators were inspired by research revealing that stress-induced UPR led to the activation of beta-site APP cleaving enzyme 1, or BACE 1, which is an enzyme that breaks apart APP to produce beta amyloid.

“The study emerged from these 3 lines of converging evidence,” Jordan-Sciutto said. “We know UPR was activated in HIV patients both on and off antiretroviral therapy; we knew that, despite antiretroviral therapy, cognitive impairment persisted in these patients; and we knew that activation of UPR lead to an increase n BACE1.”

The investigators sought to determine if and how neuronal damage arises from antiretroviral drug treatment, and to ascertain the role of BACE1. The effects of protease inhibitors were investigated using 2 animal models. The investigators then probed the mechanism of action among cells in culture.

To confirm that the cause of neuronal damage was the drugs, and not the virus itself, the investigators examined a population of macaques, some of which had SIV. The results showed SIV-positive animals treated with the protease inhibitors had increased expression of APP in their neurons, an indicator of damage. Additionally, there was an increased BACE1 compared with the untreated macaques.

These findings were confirmed after investigators administered ritonavir and saquinavir to healthy adult mice, resulting in significant increases in BACE1.

Administering ritonavir or saquinavir to the cell cultures at doses equivalent to those seen in the blood of treated humans, lead to a dramatic increase in molecular markers associated with UPR, as well as increases in BACE1 expression, the authors noted.

The increase in BACE1 directly resulted in an increase in APP processing. However, the damage caused by ritonavir was prevented after the investigators applied an inhibitor or BACE1 to rat brain cells in culture.

“Putting this together with our earlier findings on oxidative stress, it appears that the drugs are triggering oxidative stress that is damaging protein and inducing the unfolded protein response,” said co-author Cagla Akay Espinoza. “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.”

Additional experiments revealed that the enzyme PERK, which played a major role in UPR, helped mediate the increase in BACE1 expression in neurons triggered by protease inhibitors, according to the study.

“We’re very interested in the role of PERK in this process,” Jordan-Sciutto said. “Targeting PERK and/or BACE1 could help contribute to a therapeutic approach to treat drug-associated cognitive disorders.”

In the future, the investigators hope to determine whether this pathway of neuronal damage applies to other HIV drugs, and how the UPR differs depending on whether it’s being induced by the virus or the drugs. Furthermore, they hope to learn how these peptides contribute to the disorders seen in Alzheimer’s disease and in HIV-associated neurocognitive disorders.