Researchers have found that commonly used antiretroviral drugs may be the cause of a number of cognitive problems.
More than 1.2 million individuals are living with HIV within the United States. Antiretroviral therapy has been key in enabling these individuals to live longer, healthier lives. However, University of Pennsylvania (UPenn) researchers have recently found that certain protease inhibitors used to treat HIV, such as ritonavir and saquinavir, may cause neuronal degeneration as a result of the production of the β-amyloid peptides, which have been linked with Alzheimer’s disease.
Although previous studies have suggested that protease inhibitors may be a contributing factor to a number of HIV-associated neurocognitive disorders, there is not much research available on exactly how these drugs can negatively impact the brain.
In this study, UPenn researchers found that the problem really has to do with how these drugs affect β-site amyloid precursor protein cleaving enzyme 1 (BACE1). “The drugs prompt an increase in the levels of the enzyme that cleaves the amyloid precursor protein, APP, to produce β-amyloid,” the underlying culprit behind neuronal damage.
According to the press release, inhibiting BACE1 offered protection to both human and rodent brain cells, which may indicate that a drug that targets this pathway could work to lessen the neuronal damage to individuals receiving antiretroviral treatment.
In the press release, senior author of the study, Kelly Jordan-Sciutto, PhD, chair and professor in the Penn School of Dental Medicine’s department of Pathology, said, “Protease inhibitors are very effective antiviral therapies, but they do not have inherent toxicities. 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.”
Although antiretroviral treatments do not cure HIV/AIDS, they slow disease progression, and thus, prolong the lives of infected individuals. Despite the fact that newer compounds are increasingly being used in frontline treatments within the United States, ritonavir and saquinavir are still an essential part of the “drug cocktail” that is the go-to treatment option in places where HIV/AIDS remains a significant problem, such as Africa and a number of other developing countries.
This isn’t the first time that Dr. Jordan-Sciutto’s team has delved into investigations regarding these protease inhibitors. In fact, previous investigations led the research team to an unsettling conclusion: protease inhibitors can have negatively impact the central nervous system. One study found that the inhibitors activated “stress-response pathways, including oxidative stress and a process called the unfolded-protein response, or UPR.” When UPR is “chronically activated” it can result in heavy cellular damage, or even death.
When speaking of the inspiration behind their research, Dr. Jordan-Sciutto said, “The study emerged from these three lines of converging evidence. 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 decided to delve deeper into their investigations, seeking to find out if and how drug treatment is actually the cause of neuronal damage as well as just how BACE1 is involved in the process. They did this by analyzing the effects of the drugs in two animal models.
The first step in their investigation was to prove that the protease inhibitors were responsible for the neuronal damage as opposed to the virus itself. To do this, they turned to a population of macaques for answers. Some of the macaques had a retrovirus that affects nonhuman primates called SIV, which shares a number of similarities with HIV. After administering treatment to the macaques, the researchers found that the macaques who were SIV-positive experienced an increase of APP and BACE1, a finding indicative of neuronal damage.
Taking their investigation a step further, the researchers gave the protease inhibitors—ritonavir and saquinavir—to healthy mice and found that the mice exhibited an increase of BACE1, thus proving that the drugs, not the virus, was behind the damage.
Using cells in culture, they found that giving doses of the protease inhibitors “equivalent to those seen in the blood of treated humans” resulted in “dramatic increases” in UPR-associated markers and BACE1 expression. The researchers were also successful in demonstrating that increased APP was a direct result of the increased BACE1. They found that through the application of a BACE1 inhibitor to rat brain cells in culture, neuronal damage caused by ritonavir was prevented.
Further experiments provided particularly interesting findings related to PERK, an enzyme that plays a key role in UPR. The researchers found that PERK “helped mediate the increase in BACE1 expression in neurons triggered by protease inhibitors.”
According to Dr. Jordan-Sciutto, “We’re very interested in the role of PERK in this process. Targeting PERK and/or BACE1 could help contribute to a therapeutic approach to treat drug-associated cognitive disorders.”
In future research, Dr. Jordan-Sciutto and her team want to find out if other drugs used to manage HIV can result in neuronal damage. In addition, they want to know how virus-induced UPR might differ from UPR induced from the antiviral drugs. Furthermore, the research team wants to further explore the link between Alzheimer’s disease and β-amyloid in order to develop further understanding on the role of β-amyloid in Alzheimer’s as well as other HIV-associated neurocognitive disorders.