Link Found Between HIV Treatment, Neuronal Degeneration [STUDY]

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Antiretroviral drugs have been life changing therapies for HIV patients, but they can also have significant side effects.

Research findings have discovered that these drugs contribute to HIV-associated neurocognitive disorders, or HAND, which can be manifested as confusion, forgetfulness, with behavioral and motor changes. But an explanation on how these drugs take a toll on the brain is still lacking.

Researchers from the University of Pennsylvania have now discovered some of the key players that cause the neuronal damage. The research finds that certain protease inhibitors, among the most effective HIV drugs, leads to the production of the peptide beta amyloid, which is often associated with Alzheimer's disease.

The drugs prompt an increase in the level of enzyme that splits the amyloid precursor protein (APP), to produce beta amyloid, which is responsible for the damage to neurons.

Inhibiting the enzyme known as BACE1, protected human and rodent brain cells from harm, so suggesting that followng the same pathway with a new drug, could reduce damage to neurons in patients on antiretroviral therapies.

According to Science Daily, Kelly Jordan-Sciutto, chair and professor in the Penn School of Dental Medicine's Department of Pathology and senior author on the study said, "Protease inhibitors are very effective antiviral therapies, but they do have inherent toxicities."

He added that the finding may cause a rethink on how these drugs are used and even make them to consider developing an adjunctive therapy to reduce some of the negative effects.

The protease inhibitors such as ritonavir and saquinavir are a key part of the drug which has reduced mortality in HIV-infected people by 50 percent. Though newer compounds serve as the major treatments for patients in the United States, these protease inhibitors remain widely used in Africa and other developing areas.

They work by blocking viral enzymes necessary for creating infectious particles that allow the virus to spread through the body. Previous investigations by Jordan-Sciutto's team discovered that protease inhibitors can have toxic effects on the central nervous system.

They researchers triggered the activation of stress-response pathways, including oxidative stress and a process called the unfolded protein response (UPR). UPR results when the cell senses misfolded or modified proteins, causing a halt in protein translation.

It is meant to protect a cell from aberrant proteins, but it can lead to cellular damage or even death when chronically activated. Even after these studies, it was still not clear whether the UPR seen in HIV patients was induced primarily as a result of the virus or the treatment, and what molecules caused it.

In addition, the researchers were intrigued by the findings of their colleague and co-author Robert Vassar of North-western University, who demonstrated that stress-induced UPR led to activation of beta-site APP cleaving enzyme 1 (BACE1), an enzyme that tears apart APP to produce beta amyloid.

The researchers investigated the effects of protease inhibitors in two animal models to determine how neuronal damage arises from drug treatment and to ascertain BACE1's role. They probed the mechanism of action in cells in culture, according to NXT Wire.

The team examined a population of macaques, some of which had SIV, a retrovirus very similar to HIV that affects non-human primates, to confirm that the drugs themselves, and not the underlying HIV infection, were responsible for neuronal damage.

They found that SIV-positive animals that had been treated had increased level of APP in their neurons, a sign of damage, and also an increased BACE1 when compared to untreated animals. They also confirmed that the drugs were the culprit causing these changes by administering ritonavir and saquinavir to healthy adult mice, which manifested significant increases in BACE1.

Turning to cells in culture, they found that administering ritonavir or saquinavir at doses which is equivalent to those seen in the blood of treated humans led to dramatic increases in molecular markers associated with UPR as well as increases in BACE1 expression.

They also noted that the increase in BACE1 led directly to an increase in processing of APP. Applying an inhibitor of BACE1 to rat brain cells in culture prevented the damage that ritonavir treatment otherwise induced.

A final set of experiments showed that an enzyme called PERK, which is a major player in UPR, helped mediate the increase in BACE1 expression in neurons triggered by protease inhibitors. The study is published in the American Journal of Pathology.