Researchers identify key mechanisms underlying HIV-associated cognitive disorders

February 3, 2015, University of California - San Diego

While antiretroviral therapies have significantly improved and extended the lives of many HIV patients, another insidious and little discussed threat looms for aging sufferers - HIV-associated neurocognitive disorders (HAND). The disorders, which strike more often in HIV patients over age 50, can result in cognitive impairment, mild to severe, making everyday tasks a challenge.

But new findings, published today by researchers at the University of California, San Diego School of Medicine, open the door to the development of new therapies to block or decrease cognitive decline due to HAND, estimated to affect 10 to 50 percent of aging HIV sufferers to some degree.

The study is published in the Feb. 4 issue of the Journal of Neuroscience. Eliezer Masliah, MD, a professor of neurosciences and pathology, is senior author; Jerel Adam Fields, PhD, a postdoctoral researcher in Masliah's lab, is first author.

"Most people know HIV affects the immune system's ability to fight disease, but they may not be aware that HIV gets into the brain and can damage brain cells," said Masliah, an investigator with the HIV Neurobehaviorial Research Center at UC San Diego.

There are several types of HAND, the most common being Mild Neurocognitive Disorder (MND). "Most of the cases we see are mild to moderate," said Masliah. But even mild cognitive problems can interfere with everyday functioning and reduce quality of life, he added, noting that sufferers may have difficulty with daily activities like balancing a checkbook or driving directions.

In their study, the researchers sought to understand the mechanisms by which HIV damages brain cells. They focused on the HIV tat protein's role in a critical disposal process, known as autophagy, in neurons. "Neurons produce a lot of proteins as part of their normal functions, some of which are damaged and need to be cleared away," said Masliah. "Autophagy acts like a garbage disposal and removes and destroys the damaged proteins."

Masliah and colleagues found that HIV tat "hijacks" the disposal process by interfering with key pathways. "HIV tat is secreted from infected cells in the brain, and subsequently enters neurons where it binds to a protein that is important for multiple autophagy pathways," explained Fields. "This binding disrupts the neuronal autophagy process, resulting in the accumulation of damaged proteins and death of the neuron. Overtime, this may lead to impaired cognitive abilities."

To counteract this disruption, Fields said the team conducted mouse studies using the cancer drug rapamycin, which has been reported to promote autophagy in other cell types. "By speeding up neuronal autophagy, we hoped to override the disruptive effects of HIV tat on the process," he said.

The experiments produced positive results. "We found that rapamycin reduced the incidence of neurodegeneration in the mice and in cell models," said Fields. While the feasibility of rapamycin as a neurological treatment in humans is currently inconclusive, Fields said the study's results are exciting because they prove, in principle, that enhancing autophagy reduces tat-induced neurodegeneration.

"By understanding the molecular underpinnings of how HIV proteins kill nerve cells, we can design drugs that will block this process," said Masliah.

Explore further: Break on through to the other side: How HIV penetrates the blood-brain barrier

Related Stories

Break on through to the other side: How HIV penetrates the blood-brain barrier

February 2, 2015
Although it is known that HIV can enter the brain early during infection, causing inflammation and memory/cognitive problems, exactly how this occurs has been largely unknown. A new research report appearing in the February ...

Researchers find HIV protein may impact neurocognitive impairment in infected patients

November 15, 2013
A protein shed by HIV-infected brain cells alters synaptic connections between networks of nerve cells, according to new research out of the University of Minnesota. The findings could explain why nearly half of all patients ...

Scientists identify a promising target for HIV/AIDS treatment

October 24, 2014
Like a slumbering dragon, HIV can lay dormant in a person's cells for years, evading medical treatments only to wake up and strike at a later time, quickly replicating itself and destroying the immune system.

Host protein levels correlate with HIV-associated neurocognitive disorder

September 9, 2014
Combination antiretroviral therapy has dramatically increased the life expectancy for HIV-infected patients. However, the prevalence of HIV-associated neurocognitive disorders, which may be triggered by inflammation in the ...

Protein induces self-destruction in cancer cells

January 21, 2015
The role of a phosphatase protein in promoting the self-destruction of healthy cells and the progression of ovarian cancer has been identified by A*STAR researchers. Known to be overexpressed in cancer cells, the protein, ...

Worse lower, higher, frequency hearing in HIV-positive adults

December 26, 2014
Adults with the human immunodeficiency virus (HIV+) had poorer lower- and higher-frequency hearing than adults without HIV infection, according to a report published online by JAMA Otolaryngology-Head & Neck Surgery.

Recommended for you

HIV vaccine protects non-human primates from infection

December 14, 2018
For more than 20 years, scientists at Scripps Research have chipped away at the challenges of designing an HIV vaccine. Now new research, published in Immunity, shows that their experimental vaccine strategy works in non-human ...

Roadmap reveals shortcut to recreate key HIV antibody for vaccines

December 11, 2018
HIV evades the body's immune defenses through a multitude of mutations, and antibodies produced by the host's immune system to fight HIV also follow convoluted evolutionary pathways that have been challenging to track.

Eliminating the latent reservoir of HIV

December 7, 2018
A new study suggests that a genetic switch that causes latent HIV inside cells to begin to replicate can be manipulated to completely eradicate the virus from the human body. Cells harboring latent HIV are "invisible" to ...

New research highlights why HIV-infected patients suffer higher rates of cancer

December 5, 2018
AIDS patients suffer higher rates of cancer because they have fewer T-cells in their bodies to fight disease. But new research examines why HIV-infected patients have higher rates of cancer—among the leading causes of death ...

Focus on resistance to HIV offers insight into how to fight the virus

November 30, 2018
Of the 40 million people around the world infected with HIV, less than one per cent have immune systems strong enough to suppress the virus for extended periods of time. These special immune systems are known as "elite controllers." ...

Patients with rare natural ability to suppress HIV shed light on potential functional cure

November 27, 2018
Researchers at Johns Hopkins have identified two patients with HIV whose immune cells behave differently than others with the virus and actually appear to help control viral load even years after infection. Moreover, both ...

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.