Image: Neurons (green) were exposed to two antiretroviral drugs, lopinavir (LPV), darunavir (DRV), vehicle (VEH) or left untreated. Exposure to lopinavir induced loss of neurons by 24 hours, while exposure to darunavir did not. Cellular nuclei are shown in blue.
By Katherine Unger Baillie, University Communications
When it comes to treating HIV/AIDS, antiretroviral drugs such as protease inhibitors can be a double-edged sword.
“Protease inhibitors are very effective antiviral therapies, but they do have inherent toxicities,” says Kelly Jordan-Sciutto, chair and professor in Penn Dental Medicine’s Department of Pathology.
These drugs, while credited with cutting in half deaths from HIV/AIDS, have been implicated in contributing to HIV-associated neurocognitive disorders (HAND). Forgetfulness, confusion, and behavior and motor changes are among the symptoms.
In recent research, including a publication in the American Journal of Pathology, Jordan-Sciutto and colleagues have found key pathways through which the therapies seem to harm the brain—pathways that could eventually be targeted by drugs to counter some of the cognitive impairments experienced by patients undergoing treatment.
Earlier studies by the Penn team generated evidence that HIV patients taking protease inhibitors had overactive stress-response pathways, including one known as the unfolded-protein response. They also knew that the unfolded-protein response could activate the enzyme BACE1. This latter finding intrigued the researchers, for BACE1 snips amyloid precursor protein to produce beta amyloid—the same molecule that clogs up the brains of Alzheimer’s patients. Perhaps, they thought, the unfolded-protein response could be generating damaging BACE1 activity in HIV patients as well.
The research team confirmed that the protease inhibitors ritonavir and saquinavir—both still widely used, especially in Africa—indeed triggered an increase in both amyloid precursor protein and in BACE1. Then, when they administered the drugs to cells in culture, they discovered increases in signs of the unfolded protein response, as well as jumps in BACE1 expression and amyloid precursor protein processing, representing neuronal damage. A BACE1 inhibitor applied to the cells prevented the drug-induced damage.
More recent work published in the Journal of Neuroimmune Pharmacology, led by Caglay Akay-Espinoza, a research assistant professor who works with Jordan-Sciutto, confirmed that certain newer generations of HIV drugs, both protease inhibitors and another class called integrase strand transfer inhibitors, can also lead to neuron damage. Jordan-Sciutto, who is also director of biomedical graduate studies at Penn, says the findings are not a reason to abandon effective HIV/AIDS therapies but do suggest that a drug that blocks BACE1 activity might put a dent in neuron damage.
“Our findings may cause us to rethink how we’re using these drugs,” she says, “and even consider developing targeted adjunctive therapies to reduce some of these negative effects.”
Katherine Unger Baillie is a Science News Officer in University Communications.