Key marker speeds up neuro-brain decline

Osteopontin might lead to treatment

Researchers continue to study the neurological processes impacting HIV-associated neurocognitive disorder (HAND), finding most recently that an inflammatory marker called osteopontin stimulates HIV replication and remains in the central nervous system despite antiretroviral therapy.1

"My focus was on the virus — looking at what the virus does," says Amanda Brown, PhD, assistant professor in the department of neurology and co-director of translational research in neuro-AIDS at the Johns Hopkins University in Baltimore, MD. Brown also is the National Institutes of Mental Health (NIMH) development co-director of the Johns Hopkins Internship in Brain Sciences.

"So we did a screen and found that osteopontin is modestly up-regulated in human macrophages," she explains. "We didn't know whether that was a response to the virus or whether the virus was inducing this factor and enhancing replication."

Investigators established an in vitro model to study it, and that's where they found that osteopontin can increase virus expression and replication, Brown says.

"That's where we found that osteopontin itself can increase virus expression and replication," she adds. "So there seems to be a feedback loop that ties in with what HIV does in its ability to commandeer defense mechanisms of the whole cells."

HIV patients with higher levels of severe HIV disease had significantly higher severity of cognitive functioning decline according to the Memorial Sloan Kettering (MSK) cognitive functioning score, Brown says.

"Before antiretroviral therapy in 1996, you'd see people with more severe neurocognitive disease; now we have a milder form of neurocognitive disorder," she adds.

Research involving osteopontin provides clues about ongoing inflammation, and osteopontin might be an important clue in developing treatment for cognitive disorders, she notes.

"People who are not infected with HIV have much lower levels of osteopontin in their cerebral spinal fluid," Brown says.

As HIV researchers and clinicians learn more about the connection between the immune system and inflammation, they can develop a clearer picture of what kind of impact HIV disease has on the human brain, she observes.

For example, it's very important to control infections in the gastro-intestinal tract, lungs, and any kind of systemic infection that could impact the brain, Brown says.

The problem is microbial translocation in which microbes that can safely exist in the gut are sent throughout the body where they wreak havoc on the brain and other areas, she explains.

"We know from animal models that HIV infection has an early impact on t-cells in the gut and affects the whole gut system, causing a massive depletion of t-cells," she adds. "Then that causes total disregulation of the microbiome, which is supposed to stay in the gut."

The influx of microbiome throughout the body leads to increased release of inflammatory markers, which leads to neurocognitive disorders, Brown says.

"For some patients it doesn't go away even when they're on therapy," she adds.

So far clinicians are left with some additional knowledge about what's going on with HAND, but no great solutions.

Several clinical trials studied different agents that investigators hoped would help decrease the inflammatory response, especially considering positive findings in primate trials. But these proved to have no efficacy in clinical trials, Brown notes.

Brown and co-investigators plan to continue research involving osteopontin, next studying signaling pathways to determine whether osteopontin signaling is determining inflammatory cascades.

"We plan to explore the effect of osteopontin on neurodegeneration," she adds.

Reference

  1. Brown A, Islam T, Adams R, et al. Osteopontin enhances HIV replication and is increased in the brain and cerebrospinal fluid of HIV-infected individuals. J Neuroviral 2011;17(4):382-392.