HIV Drugs Could Cause Neurodegeneration


Treatment with protease inhibitors could result in HIV-associated neurocognitive diseases.

Findings from a new study suggest that antiretroviral drugs that treat HIV could cause neuronal degeneration.

Antiretroviral drugs are used to reduce the HIV viral load in the patient’s body. Doing so will typically reduce the risk for disease transmission and prevent symptoms associated with HIV.

While these drugs have been largely beneficial, new evidence may link these drugs with HIV-associated neurocognitive diseases. Symptoms of these diseases include forgetfulness, confusion, behavioral changes, and altered motor functions. However, a better understanding of how these drugs affect the brain have previously been unknown.

The authors of the study, which was published by the American Journal of Pathology, suggest that protease inhibitors cause the production of amyloid beta, which is associated with Alzheimer’s disease.

The drugs trigger an increase in the enzyme that cleaves the amyloid precursor protein to create amyloid beta. Unfortunately, these drugs are among the most effective treatments for HIV, and are widely used.

However, the authors discovered that inhibiting the BACE1 enzyme was able to protect both human and rodent brain cells from harm. This could lead to novel antiretroviral drugs that do not damage neurons, according to the study.

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

Protease inhibitors, such as ritonavir and saquinavir, are critical components of a multi-drug cocktail that has reduced mortality in patients with HIV by 50%. These drugs work by blocking HIV enzymes that are necessary to spread the infection throughout the body.

While newer drugs are being developed and marketed in the United States, these protease inhibitors continue to be used in Africa and other areas that are significantly affected by HIV/AIDS, according to the study.

Previous research conducted by this team of investigators revealed potentially toxic effects on the central nervous system. For example, they found that the drugs triggered the activation of oxidative stress and unfolded-protein response (UPR), which results in a halt in protein translation. The UPR process is meant to protect the cell from abnormal proteins, but can lead to cell death if activated too frequently.

However, the findings did not determine whether UPR occurred in these patients from the virus or the treatment, and which molecules could stop it. Additionally, researchers were also interested in findings from another team that showed that stress-induced UPR activated the BACE1 enzyme.

"The study emerged from these three lines of converging evidence," Dr Jordan-Sciutto said. "We knew 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 in BACE1."

The researchers first examined the effects of protease inhibitors in animal models and in cultured cells to determine how neuronal damage may arise from treatment, and to discover BACE1’s role in the process, according to the study.

To show that protease inhibitors—and not HIV— were causing neuronal damage, the researchers examined macaques, some of which were infected with SIV. The investigators discovered that SIV-positive macaques that were treated had increased expression of amyloid precursor protein in neurons, and an increase in BACE1 compared with untreated macaques, according to the study.

The researchers also confirmed that the use of ritonavir and saquinavir were responsible for these changes in mice as well. Additionally, administration of these drugs to cells in culture at doses equivalent to human doses lead to increased levels of markers associated with UPR, and increased BACE1 expression, according to the study.

It was also discovered that an increase in BACE1 resulted in an increase in amyloid precursor protein. By administering a BACE1 inhibitor to rat brain cells, the researchers found that cells remained unharmed.

"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."

In their final experiment, the investigators found that the PERK enzyme, which plays a role in UPR, helped increase BACE1 expression in neurons, according to the study.

These findings open up numerous research possibilities, and the investigators hope to explore whether these pathways are involved with other HIV drugs. They also would like to conduct other studies to determine how the UPR differs depending if it is triggered by HIV or protease inhibitors.

The researchers said they are also interested in learning more about the connection between amyloid beta, amyloid precursor protein, and Alzheimer’s disease, and how they relate to HIV-associated neurocognitive diseases, the study concluded.

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

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