Scavenger cells could be key to treating HIV-related dementia

Bacteria-eating cells that generally fight infection may cause dementia in HIV patients, University of Florida and University of California at San Francisco researchers have found.

Macrophages, long-living white blood cells often considered the scavengers of the immune system, actually may damage a part of the brain where many memories are stored in their attempt to attack the virus there, according to findings reported in the Journal of Virology this month.

Researchers found that HIV-infected macrophages in the brain continuously travel to the temporal lobe, a part of the brain Alzheimer's disease often damages. Because the virus mutates nearly 100 times faster in the temporal lobe than other parts of the brain, attacking macrophages migrate there in a constant stream, causing harmful inflammation.

Nearly 15 percent of HIV patients develop dementia as their disease progresses. But understanding the routes macrophage cells take in the brain could help researchers find ways to block the migration and prevent HIV-associated dementia, said Marco Salemi, a UF assistant professor of pathology and immunology and an author of the study.

"In a way, it's not the virus that directly causes the dementia," Salemi said. "It's the fact that there is this continuous migration of infected macrophages to the temporal lobe. The virus mutates much faster there, the macrophages keep accumulating and keep creating this inflammation that leads to dementia."

Macrophages also may explain why current drugs cannot kill the virus that causes AIDS.

Researchers have known for years how HIV replicates in T cells, also part of the immune system. But most are just beginning to understand how the virus affects macrophages, said Dr. Michael S. McGrath, a UCSF professor of pathology and laboratory medicine who co-authored the study.

"It's likely the oldest (form of the) virus lives in a macrophage in the brain and most virus strains evolve from that," McGrath said. "Imagine having cells, already infected, that live as long as you do."

Current antiretroviral drugs block HIV from replicating in new T cells, but don't kill the virus in infected macrophages. And the drugs cannot stop the virus from evolving into new forms, McGrath said. Because the virus mutates faster than other cells in the body, it also can develop resistance to these drugs, Salemi said.

Even the HIV already in an infected person's brain is not one single virus, but rather populations of slightly different viruses that infect different parts of the brain, the findings show.

"We agree there are different strains that populate different regions of the brain," said Dr. Francisco Gonzalez-Scarano, chairman of the University of Pennsylvania neurology department. "We've done similar studies in monkeys."

To obtain their findings, the researchers studied different regions of the brain of a person who died with HIV-associated dementia using specimens from the AIDS and Cancer Specimen Resource at UCSF. They also used a new computer-based research tool to study the results. Dubbed phylodynamic analysis, this new method links traditional ways of studying the virus to give researchers a more comprehensive understanding, which Salemi says is crucial to analyzing the ever-changing disease.

"If we really want to understand what happens to a person infected with this disease, we need to develop new tools," he said. "We can put together all these different resources and describe how the virus changes over time and try to understand why this particular damage happens"

But these results are just a first step, Salemi said. The team is now analyzing brains from 10 people, some who died with HIV-associated dementia and others who did not.

The well-known cocktail of antiretroviral drugs prescribed to most HIV patients has cut the number of HIV-associated dementia cases reported each year, Gonzalez-Scarano said. However, this is because the drugs slow the progression of the disease, he said. Patients still have the same chance of developing dementia later, as the disease advances.

That's one of the reasons why the researchers say developing drugs that target macrophages as well as T cells is important. These drugs could provide better treatments for dementia and potentially lead to a way to "eradicate HIV-1 infection," the study states.

"You can't cure (HIV) with antiretroviral therapy (alone)," McGrath said.

Researchers from the University of California at Irvine, the University of Oxford and Gene Johnson Inc. also contributed to the study, which was funded by the National Science Foundation, the National Institutes of Health and the National Cancer Institute.