Rappaport and his collaborators at the Center have been focusing on the role of macrophages--large, long-lived cells of the immune system that travel throughout the body and ingest foreign antigens to protect against infection--in the development of HIV dementia complex.
"Basically, HIV infection of the central nervous system and the brain is really the cause of severe HIV dementia, and currently 10 percent of AIDS patients get this type of dementia," says Rappaport. "This figure has dropped from 20 to 30 percent because of the success of highly aggressive anti-retroviral therapy. This figure might increase if drug therapy begins to fail in patients who are on therapeutic regimens for longer periods of time.
"For many years, there has been a 'Trojan Horse' model, which holds that these macrophages might enter the brain early during infection, secretly carrying the AIDS virus and allowing the long-term resident macrophages of the brain [the microglia] to be infected," says Rappaport.
Rappaport believes that, during AIDS, the major invasion of HIV occurs late in the disease. Trafficking and production of macrophages in the brain increase during this time. He hypothesizes that these increases come from bone marrow, because, he says, "there's an activated subset in blood that goes way up in HIV patients with dementia. These macrophages are more invasive in other organs as well.
"So the grant we've received is really to look at the issue of generation and trafficking of these macrophages, where they're being expanded in AIDS, and how they get into the brain," he adds. "Also, we want to determine how they get into other organs as well."
Rappaport and his collaborators--who include Center director Kamel Khalili, Ph.D.; Sidney Croul, M.D.; and doctoral student Tracy Fischer-Smith--have also examined other body organs of patients who have developed HIV dementia complex and found the infected macrophages not only in the brain, but in the liver, kidneys, lymph nodes and spleen as well.
"We've really seen a multi-organ invasion of these cells," he says.
Rappaport believes that since the macrophages are such long-lived cells, they are providing a hidden reservoir for productive HIV infection.
"When you put an HIV patient on drugs or drug therapy, the virus goes way down to often undetectable levels," notes Rappaport. "But when you take them off the drugs, the infection comes back. It may very well be these macrophages where the infected cells are hiding."
Rappaport believes the researchers' findings will be important not only for patients with HIV dementia, but also for AIDS research in general.
"These macrophages are probably an important reservoir where the virus hides in the tissues and is probably the most resistant reservoir of the virus to get rid of since these cells are so long-lived," he says. "And being so long-lived you don't eliminate them with drug therapies.
"Maybe there's a way to target and destroy these macrophages or at least prevent their expansion," he adds. "We're really coming at this from a different angle, in that we're looking at the invasion of these cells into the brain. This approach could lead to looking at different therapies other than conventional anti-retroviral drugs."