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Temple Scientists Looking to Cancer Drug to Help Mental Decline with HIV
Scientists at Temple University School of Medicine are hoping a promising group of cancer drugs will help slow the mental decline all-too-common in people infected with HIV, the virus that causes AIDS.
Buoyed by a new five-year grant for approximately $2.3 million from the National Institute of Mental Health, part of the National Institutes of Health, Yuri Persidsky, MD, PhD, Professor and Chair of the Department of Pathology and Laboratory Medicine, is studying the use of anticancer drugs called PARP inhibitors, which make cells susceptible to DNA damage, and which currently are being tested in patients with breast and ovarian cancer. PARP, or poly(ADP-ribose) polymerases, are DNA-repair proteins that are also important to the integrity of the human genome.
According to Dr. Persidsky, infection with HIV is known to cause a slow mental decline. HIV infection can cause brain inflammation, and include an over-production of immune factors by HIV-infected white blood cells that migrate to the brain.
Such cognitive decline is temporarily halted when patients infected with HIV receive cART – combination anti-retroviral therapy – a cocktail of drugs that has been largely responsible for rendering HIV infection a chronic illness. However, while the drugs dramatically reduce the virus' ability to reproduce, the cognitive problems – termed HAND, or HIV-associated neurocognitive disorder – eventually return.
"After the widespread use of cART began, the neurocognitive problems initially went away in individuals with HIV infection," Dr. Persidsky said. "But these problems emerged again, years later, after years of chronic inflammation and exposure to these factors. Now people are living longer and we are beginning to see these problems return."
A Weakened Blood-Brain Barrier
HIV infection and the resulting chronic inflammatory condition, he said, damages the blood-brain barrier, allowing the entry of white blood cells called monocytes and leukocytes. The blood-brain barrier is a series of blood vessels that act as a highly selective filter. It blocks certain drugs, chemicals and viruses from reaching the central nervous system from the bloodstream, yet plays an important role in supplying nutrients to the brain.
"This cognitive decline in HIV patients has been shown to correlate with injury to the blood-brain barrier and has been documented by imaging and blood serum studies showing inflammatory factors penetrating the barrier and damaging it," Dr. Persidsky said.
He is interested in "approaches using PARP inhibitors that would allow us to preserve or tighten the barrier or protect it from destruction by inflammatory factors or white blood cells." In a series of studies, he and his colleagues showed that PARP inhibitors could repair some of the damage to the blood-brain barrier and reduce the ability of white blood cells to get inside. In the laboratory, they have been able to model what will happen when the barrier is disrupted, and show that PARP inhibitors can help restore it.
The researchers plan to focus on the effects of PARP inhibitors on the barrier. "We think that in the blood-brain barrier, interactions between monocytes and endothelial cells (cells that line the inside of blood vessels) that are activated by production of inflammatory factors cause the barrier to leak," he said, adding that the team will examine combinations of PARP inhibitors and their effects on endothelial cells and the production of inflammatory molecules.
Dr. Persidsky also plans to study the ability of PARP inhibitors to block virus replication, and what role if any the drugs may play in preventing the migration of white blood cells into the brain.
Using animal models, the researchers plan to image tiny blood vessels in the brain and measure changes to the blood-brain barrier, he explained. They will use mice lacking immune systems – a typical model used by many researchers – to reproduce changes similar to HIV brain infection, such as the movement of white blood cells and the disruption of the blood brain barrier. "It allows us to measure the progress of disease and see if in a relevant model we can suppress virus replication," he said.
Findings May Have Implications for Treating Other Diseases
The research has broader implications for a wide range of diseases, he noted. "Though we are examining the relationship between HIV and neurological decline, our results could be widely applicable to the basic understanding of any inflammatory disease and how it affects the brain."
An overactive inflammatory response could be responsible for other health problems, he said, including a premature buildup of atherosclerotic plaque, which is more prevalent in HIV-positive individuals. "If the changes associated with these responses could be better understood and controlled, perhaps we could come up with better prevention efforts."
"Very little is known about the potential use of PARP inhibitors," Dr. Persidsky said, and few scientists are studying PARP inhibitors and HIV-associated cognitive decline. "We are finding very high activity and some sort of biological phenomenon that may teach us something more beyond HIV infection," noting other viral infections, such as hepatitis C virus, are linked to such cognitive effects.
"This is an underappreciated problem, particularly because very few people are dying of HIV now," Dr. Persidsky said. "We need to bring more attention to the longer-term problems related to HIV infection."
His co-investigators include Servio H. Ramirez, PhD, Assistant Professor of Pathology and Laboratory Medicine at Temple University School of Medicine and Marlys Witte, MD, Professor of Surgery at the University of Arizona.
Date Published: Tuesday, September 04, 2012
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