Defending the Brain Against HIV
Date: June 1, 2009
Formerly a successful finance professional, the man now couldn’t balance his checkbook, much less keep track of the financial transactions he had supervised for 25 years. A long-term HIV infection, which antiretroviral drugs had kept in check for decades, was now taking its toll — on his brain. He began forgetting to take his medications. Even his judgment was impaired, leading him to have unprotected sex.
The man had HIV-associated neurocognitive disorder (HAND), and the number of cases like his is increasing substantially as patients with chronic HIV survive for longer periods of time, says Neurology Department Director Justin McArthur. He and biochemist Joe Steiner are leading a research effort to search for drugs that can protect the brain and central nervous system from the damage of HIV. Their studies are based at the Hopkins NIMH Center for Novel Therapeutics of HIV-Associated Cognitive Disorders.
“It’s probably not HIV replication alone that causes the neurological damage,” says Steiner. Instead, viral proteins appear to trigger inflammation in the brain, which in turn leads to oxidative stress and a host of other damaging effects.
As a starting point in the team’s research, Steiner developed a model of oxidative stress in cultures containing neurons and glial cells. He then used the model to screen 2,000 FDA-approved drugs, searching for agents that could shield the cells from oxidative stress and thus enhance cell survival.
“We identified about 25 to 30 compounds that looked interesting,” says Steiner. He then narrowed down that list, rejecting any that were of low potency, a detriment in a drug that must penetrate the blood-brain barrier. Resveratrol, for example, the red wine antioxidant, showed promising neuroprotective results, but only in extremely high concentrations. “You’d have to drink 10 bottles of wine to see an effect,” Steiner says jokingly.
One set of compounds, however, proved both neuroprotective and highly potent — antidepressants, particularly the SSRIs. Just nanomolar concentrations of these drugs protected the cell cultures from oxidative stress.
Steiner has also tested various SSRIs in a mouse model; the results show that the compounds safeguard mice neural cells from the damaging effects of a key HIV protein. Eventually, the team may pursue a clinical study. However, if antidepressants do help shield the brain from HIV’s neurocognitive damage, then HIV patients who already happen to be taking SSRIs may be receiving this extra benefit. “We’re going back through patient records to try to tease out whether we see some effect,” says McArthur.
Among patients with chronic HIV, 20 percent to 25 percent will develop neurocognitive problems as a consequence of their infection, notes McArthur. “Some degree of those problems might be reversible if treated with a neuroprotective agent. Our ultimate goal is to get people back to as normal function as possible.”
For more information, visit the Johns Hopkins Neuro-AIDS web site.