Apr. 28, 2005 By studying animals, Johns Hopkins researchers have discovered that the antibiotic minocycline might help alleviate HIV's negative effects on the brain and central nervous system, problems that can develop even though antiretroviral therapy controls the virus elsewhere in the body.
Five monkeys infected with simian immunodeficiency virus (SIV), a very close relative of HIV, and treated with minocycline had less damage to brain cells, less brain inflammation, and less virus in the central nervous system than six infected monkeys that received no treatment, the researchers report in the April 27 issue of the Journal of the American Medical Association.
"In people, antiretroviral treatments do a great job of controlling HIV in blood, but most of the drugs don't cross the blood-brain barrier very well," says Christine Zink, D.V.M., Ph.D., professor of comparative medicine at the Johns Hopkins University School of Medicine. "As a result, even though the infection seems to be controlled, it may still cause damage in the brain. And because people are living with HIV longer than ever, the prevalence of neurological damage is increasing. Currently, there's no drug to treat it directly."
In use for more than 30 years, minocycline was specifically designed to cross the blood-brain barrier, the biological "wall" that limits what can pass from the blood into the brain. Other researchers have reported that this antibiotic can protect brain cells in animal models of other diseases -- multiple sclerosis, amyotrophic lateral sclerosis, Alzheimer's disease, stroke and more. The drug is being tested in early clinical trials for some non-HIV-related conditions.
"Last year we discovered that SIV triggers some of the same biological pathways of cell death and inflammation as these other diseases," says Sheila Barber, Ph.D., assistant professor of comparative medicine. "Testing minocycline in our animal model of HIV infection was really a logical next step."
A multicenter clinical trial is being planned to test whether minocycline has the same effects in HIV-infected people as it does in SIV-infected monkeys, but it is not expected to start until sometime next year.
"It is too early to recommend minocycline for patients," emphasizes Ned Sacktor, M.D., an associate professor of neurology at the Johns Hopkins Bayview Medical Center who wasn't involved with the current study, but who is one of the physicians planning the clinical trial. "One needs to proceed with a clinical research trial first to prove its safety and efficacy against HIV-associated cognitive impairment."
SIV and HIV both affect the same tissues in the same way and use the same tricks to infect cells and outwit treatments, but SIV infects only non-human primates, and HIV only infects people. Antiretroviral drugs target and interfere with the viral proteins needed to accomplish this.
In contrast, minocycline doesn't target the virus or its proteins. While they're still working out the details, the researchers have shown that minocycline "calms down" as yet undefined biological pathways that involve two specific proteins -- MCP-1 and p38 -- implicated in damage in neurodegenerative diseases.
The MCP-1 protein, when secreted from brain cells under attack from HIV or SIV, attracts infection-fighting cells known as macrophages, which then enter the brain. The influx of these cells contributes to swelling and inflammation known as encephalitis. The other protein, p38, helps trigger a series of events that result in a cell's programmed death, called apoptosis.
Only one of the five treated monkeys showed any signs of encephalitis, and that monkey's condition was deemed mild by a set of standard measures. After the same amount of time -- 84 days after infection -- five of the six untreated monkeys had evidence of moderate or severe encephalitis and much more physical evidence of damage to brain cells, the researchers report.
"The infection in the animal model is predictable and aggressive, so we can get meaningful data by studying fewer animals," says Zink, who was on the team that developed the model about six years ago. "It's a really demanding test of a potential treatment for HIV."
The animal model has already helped improve understanding of how HIV might affect the brain, and this is the first time it's been used to test a potential treatment. Studies with the animals are augmented by laboratory experiments with cells to clarify observations.
Notably, these laboratory experiments have shown that minocycline somehow suppresses replication of HIV and SIV in macrophages -- the immune cells recruited to the brain during HIV infection -- and lymphocytes -- immune cells that carry "sleeping" HIV and SIV even when antiretroviral treatment is effective.
"If this preliminary observation holds up, minocycline could be really important for treating HIV infection in developing countries where access to traditional antiretroviral drugs is very limited," says Zink. "Most of the 40 million people with HIV infection live in these countries."
The research was funded by the National Institute of Mental Health and the National Institute of Neurological Disorders and Stroke. Authors on the paper are Zink, Barber, Jennifer Uhrlaub, Jesse DeWitt, Tauni Voelker, Brandon Bullock, Joseph Mankowski and Janice Clements of Johns Hopkins; and Patrick Tarwater of the University of Texas Health Science Center's School of Public Health, El Paso, Texas.
Zink and Barber are named as inventors on a pending patent application for minocycline to treat HIV infection. The patent will be held by The Johns Hopkins University.
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