HIV Medications Linked to Increase in Alzheimer’s Disease Proteinby Viatcheslav Wlassoff, PhD | May 8, 2017
A class of drugs called protease inhibitors have been lifesaving for people with the human immunodeficiency virus (HIV). However, these medications come with a long list of side effects that may include impairments in cognitive function. How protease inhibitors might cause cognitive side effects has remained a mystery for some time. New research from the University of Pennsylvania is beginning to shed light on the answer, and it lies in a protein that is one of the main components of Alzheimer’s disease.
Protease inhibitors work to treat HIV by preventing replication of the HIV virus. The drugs block an enzyme called HIV protease, which cleaves the protein precursors required to produce new viral particles. Inhibiting HIV protease thus prevents the spread of the virus throughout the body. Since the approval of these drugs for clinical use in 1995, the rate of deaths from HIV has declined drastically. A typical HIV patient takes a combination of protease inhibitors and other medications to counter the development of drug-resistant HIV strains.
Side effects caused by protease inhibitors are common. These include dyslipidemia, hypercholesterolemia, metabolic syndrome, and, potentially, cognitive dysfunction. HIV-associated cognitive disorders, abbreviated HAND, include a spectrum of symptoms such as forgetfulness, confusion, and behavioral and motor changes. While the HIV virus itself is believed to play a role in causing HAND symptoms, the drugs used to treat the virus, including protease inhibitors, have also been implicated in the development of HAND. Until now, little was known about how protease inhibitors might cause cognitive side effects, and therefore, how such symptoms might be prevented.
Recent research from the University of Pennsylvania has shed new light on the mechanism by which protease inhibitors might impair cognitive function. Work by Kelly Jordan-Sciutto and colleagues in the Department of Pathology at the University of Pennsylvania has demonstrated that protease inhibitors increase levels of the peptide beta amyloid in the brain. Excessive levels of beta amyloid can impair the way brain cells function.
Beta amyloid protein is commonly known for playing a major role in Alzeheimer’s disease and several other neurological diseases, including Lewy body dementia, inclusion body myositis, and cerebral amyloid angiopathy. In Alzheimer’s disease, beta amyloid forms plaques or clumps of protein that give rise to deposits outside of brain cells, causing impairments in cell function. Increased levels of beta amyloid and its precursor protein – amyloid precursor protein (APP) – have also been observed in the brains of HIV-infected patients.
Jordan-Sciutto’s team had previously found that HIV drugs such as protease inhibitors can be toxic to neurons. They showed that some of these toxic effects were caused by damage to the DNA of the cell’s energy-generating cells, called mitochondria, which are located in the endoplasmic reticulum (ER). ER stress is known to activate the cell’s unfolded protein response (UPR) that increase the level of a protein called BACE1. In turn, BACE1 increases levels of beta amyloid by cleaving its precursor protein, APP.
Jordan-Sciutto theorized that because protease inhibitors cause ER stress, they might also increase beta amyloid by activating the UPR, and thus BACE1 and APP downstream. Their most recent study, published in the American Journal of Pathology, explored these questions further by examining whether protease inhibitors change the levels of beta amyloid and other cellular proteins that regulate its production.
To explore this question, a group of macaques were infected with the form of HIV found in monkeys, called simian immunodeficiency virus (SIV). Monkeys were then treated with either a cocktail of protease inhibitors or a placebo. The brains of the monkeys were examined 160 days following infection.
The results of the experiments showed that SIV-infected monkeys treated with protease inhibitors had much higher levels of beta amyloid in their neurons than infected monkeys who did not receive the drug. Infected drug-treated monkeys also showed increased levels of the amyloid beta precursor protein. As Jordan-Sciutto predicted, these monkeys also had increased levels of BACE1.
Interestingly, 90% of the placebo-treated animals developed signs of neurological dysfunction by 12 weeks of treatment, whereas the animals treated with the drug cocktail did not display any of these symptoms. This raises the question of whether the observed increases in amyloid beta protein in the drug-treated animals are pathological; that is, whether this amount of beta amyloid can cause symptoms. To date, the researchers have not studied monkeys treated with protease inhibitors in the absence of SIV infection in order to assess the effects of the drug alone.
To partly address this problem, the researchers also studied the effect of protease inhibitors on the unfolded protein response (UPR) in cultured cells derived from rat glial cells and human fetal tissue. Protease inhibitors increased the expression of markers associated with UPR activation and increased BACE1 in the cultured cells, which led to an increase in the cleavage of APP and subsequent cell damage. Conversely, treatment with a drug that inhibited BACE1 prevented this cell damage. Finally, the researchers showed that another enzyme, called PERK, was also a key player in the unfolded protein response that led to the increase in BACE1 levels.
These novel findings provide a clear mechanism for protease inhibitor brain toxicity in patients with HIV, suggesting that these drugs may in fact contribute to the development of HIV-associated cognitive disorders by increasing beta amyloid. Despite these neurotoxic effects, protease inhibitors will remain a mainstay for the treatment of HIV, as they have profoundly improved the quality of life and extended the lifespan of patients. The results of these studies suggest that potential new therapies targeting the proteins BACE1 and PERK could prevent the cognitive side effects of protease inhibitors.
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