Scavenger Cells Could Be Key To Treating HIV-related Dementia

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

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

Nearly 15 percent of HIV patients develop dementia as theirdisease progresses. But understanding the routes macrophage cells takein the brain could help researchers find ways to block the migrationand prevent HIV-associated dementia, said Marco Salemi, Ph.D, a UFassistant professor of pathology and immunology and an author of thestudy.

"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 ofinfected macrophages to the temporal lobe. The virus mutates muchfaster there, the macrophages keep accumulating and keep creating thisinflammation 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, alsopart of the immune system. But most are just beginning to understandhow the virus affects macrophages, said Michael S. McGrath, M.D., Ph.D,a UCSF professor of pathology and laboratory medicine who co-authoredthe study.

"It's likely the oldest (form of the) virus lives in a macrophage inthe 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 cannotstop the virus from evolving into new forms, McGrath said. Because thevirus mutates faster than other cells in the body, it also can developresistance to these drugs, Salemi said.

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

"We agree there are different strains that populate different regionsof the brain," said Francisco Gonzalez-Scarano, M.D., chairman of theUniversity of Pennsylvania neurology department. "We've done similarstudies in monkeys."

To obtain their findings, the researchers studied different regions ofthe brain of a person who died with HIV-associated dementia usingspecimens from the AIDS and Cancer Specimen Resource at UCSF. They alsoused a new computer-based research tool to study the results. Dubbedphylodynamic analysis, this new method links traditional ways ofstudying the virus to give researchers a more comprehensiveunderstanding, which Salemi says is crucial to analyzing theever-changing disease.

"If we really want to understand what happens to a person infected withthis disease, we need to develop new tools," he said. "We can puttogether all these different resources and describe how the viruschanges over time and try to understand why this particular damagehappens"

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

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

That's one of the reasons why the researchers say developingdrugs that target macrophages as well as T cells is important. Thesedrugs could provide better treatments for dementia and potentially leadto 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 Universityof Oxford and Gene Johnson Inc. also contributed to the study, whichwas funded by the National Science Foundation, the National Institutesof Health and the National Cancer Institute.