Molecular mechanism behind HIV-associated dementia revealed

January 5, 2018 by Will Doss, Northwestern University
The interaction between APP (red) and GAG (green) in the cell. Credit: Northwestern University

For the first time, scientists have identified and inhibited a molecular process that can lead to neurodegeneration in patients with HIV, according to a Northwestern Medicine study published in Nature Communications.

Mojgan Naghavi, Ph.D., associate professor of Microbiology-Immunology, was senior author on the study, and Qingqing Chai, Ph.D., a postdoctoral fellow in Naghavi's lab, was the lead author.

Previous studies have found elevated levels of toxic beta-amyloid protein in the brains of patients with human immunodeficiency virus (HIV), causing HIV-associated neurocognitive disorder (HAND). While can greatly slow down HIV progression, up to 50 percent of these patients exhibit milder forms of HAND. Buildup of beta-amyloid is thought to be a major contributor to neurodegeneration in a variety of dementia-associated diseases, especially Alzheimer's, but how and why beta-amyloid is produced in HIV-infected patients and its contribution to HAND was a mystery, Naghavi said.

"The HIV virus cannot infect neurons because they don't have the right receptors," said Naghavi, who is also a member of the Robert H. Lurie Comprehensive Cancer Center of Northwestern University. "We've known about elevated beta-amyloid levels for a long time, but nobody knew how or why the protein was overproduced in response to infection."

The first clue came when Naghavi and her colleagues preformed a large-scale assay looking for unusual interactions between cellular proteins and Gag, an important HIV protein. A number of proteins were shown to bind with Gag, but one stood out—membrane-associated amyloid precursor protein (APP), a protein that can be processed to produce the toxic beta-amyloid protein.

"We put two and two together: We knew APP is a precursor to beta-amyloid, so we looked for APP and found increased processing of this protein into beta-amyloid in infected macrophages and microglia," Naghavi said.

Macrophages and microglia are two types of non-neuronal brain cells that HIV infect, often functioning as reservoirs of the disease in the brain, according to Naghavi. In those cells, APP interferes with HIV infection, and in response, HIV tries to circumvent that barrier.

During infection of a microglia or macrophage cell, HIV's Gag promotes processing of APP, reducing resistance to cell takeover, which also has the side-effect of producing toxic beta-amyloid proteins, Naghavi said.

"By binding to APP, somehow Gag drags it into cell membrane regions called lipid rafts, where there are enzymes that promote processing of APP into beta-amyloid," she said. "This is the first time we've showed HIV is trying to overcome a block that is induced by APP in microglia and macrophages."

To reduce buildup of beta-amyloid, the scientists targeted the enzyme that cleaves APP, called gamma secretase. A simple inhibitor that blocked APP processing produced dual benefits by inhibiting infection and reducing beta-amyloid production, according to Naghavi.

When the drug blocks APP processing, it reduces beta amyloid and increases APP compared to non-drugged models. This results in the combined benefits of reduced neurodegeneration and sustaining APP's original function of blocking infection.

"We've opened the door for how these drugs might be used to block both HIV replication and treat HIV-associated dementia," Naghavi said. "It would also be interesting to investigate whether APP affects replication of other neurotropic viruses, for example Zika or Cytomegalovirus."

However, translating these findings into a drug that works in patients is still a ways off. Compounds that have the intended effect may also be toxic in humans or have other undesirable side effects, so finding non-toxic drugs that can modulate gamma-secretase is the next step towards an actionable treatment.

HIV patients are living longer thanks to more effective treatments, so there's a growing need to address the HIV-specific chronic health issues they encounter as they age, said Naghavi.

"HIV patients on combination antiretroviral therapy have close to a normal life, but they are still suffering from diseases like HAND," Naghavi said. "This is just the beginning."

Explore further: One step closer toward a treatment for Alzheimer's disease?

More information: Qingqing Chai et al. HIV-1 counteracts an innate restriction by amyloid precursor protein resulting in neurodegeneration, Nature Communications (2017). DOI: 10.1038/s41467-017-01795-8

Related Stories

One step closer toward a treatment for Alzheimer's disease?

October 18, 2017
Scientists at the Massachusetts General Hospital (MGH), in collaboration with colleagues at the University California, San Diego (UCSD), have characterized a new class of drugs as potential therapeutics for Alzheimer's disease ...

Novel perspectives on anti-amyloid treatment for the prevention of Alzheimer's disease

July 27, 2017
For decades researches have been investigating the underlying foundations of Alzheimer's disease to provide clues for the design of a successful therapy. This week, VIB/KU Leuven scientists have published breakthrough insights ...

HIV infection hijacks intracellular highways

September 27, 2017
A Northwestern Medicine study found the human immunodeficiency virus (HIV) uses proteins called diaphanous-related formins (DRFs) to hijack the cytoskeleton of healthy cells, findings that deepen the understanding of HIV ...

'Pac-Man' gene implicated in Alzheimer's disease

July 26, 2016
A gene that protects the brain from the harmful build-up of amyloid-beta, one of the causative proteins implicated in Alzheimer's disease, has been identified as a new target for therapy by NeuRA researchers.

Alzheimer protein's structure may explain its toxicity

May 7, 2015
Researchers at the University of Illinois at Chicago have determined the molecular structure of one of the proteins in the fine fibers of the brain plaques that are a hallmark of Alzheimer's disease. This molecule, called ...

Recommended for you

Anxiety: An early indicator of Alzheimer's disease?

January 12, 2018
A new study suggests an association between elevated amyloid beta levels and the worsening of anxiety symptoms. The findings support the hypothesis that neuropsychiatric symptoms could represent the early manifestation of ...

One of the most promising drugs for Alzheimer's disease fails in clinical trials

January 11, 2018
To the roughly 400 clinical trials that have tested some experimental treatment for Alzheimer's disease and come up short, we can now add three more.

Different disease types associated with distinct amyloid-beta prion strains found in Alzheimer's patients

January 9, 2018
An international team of researchers has found different disease type associations with distinct amyloid-beta prion strains in the brains of dead Alzheimer's patients. In their paper published in Proceedings of the National ...

Advances in brain imaging settle debate over spread of key protein in Alzheimer's

January 5, 2018
Recent advances in brain imaging have enabled scientists to show for the first time that a key protein which causes nerve cell death spreads throughout the brain in Alzheimer's disease - and hence that blocking its spread ...

Molecular mechanism behind HIV-associated dementia revealed

January 5, 2018
For the first time, scientists have identified and inhibited a molecular process that can lead to neurodegeneration in patients with HIV, according to a Northwestern Medicine study published in Nature Communications.

Mice with frequent flier miles advance the Alzheimer's cause

January 4, 2018
Alzheimer's disease wreaks emotional havoc on patients, who are robbed of their memories, their dignity, and their lives. It's financially devastating as well: care for Alzheimer's patients is predicted to top $1 trillion ...

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.