When it comes to treating HIV/AIDS, antiretroviral drugs such as protease inhibitors can present 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 the School of Dental Medicine’s Department of Pathology.
These drugs, while credited with cutting deaths from HIV/AIDS in half, have been implicated in contributing to HIV-associated neurocognitive disorders (HAND). Forgetfulness, confusion, and behavior and motor changes are among the symptoms.
Jordan-Sciutto and colleagues have investigated the link between HIV drugs and these ailments, and in a publication in the American Journal of Pathology, they reveal a key pathway through which the therapies seem to harm the brain—one that could eventually be targeted by a drug to counter some of the cognitive impairments experienced by patients undergoing treatment.
Earlier studies by Jordan-Sciutto and her collaborators generated evidence that HIV patients under treatment with protease inhibitors had overactive stress-response pathways, including a pathway 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.
In their current work, the research team used two animal models to confirm that 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.
Jordan-Sciutto says the findings are not 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, and even consider developing an adjunctive therapy to reduce some of these negative effects,” she says.