Novel Compound Inhibits HIV Replication In Cell Cultures, Suggesting Possible New Type Of AIDS Drug

A research team led by pediatric immunologists at The Children’s Hospital of Philadelphia announced its results in the March 27 Proceedings of the National Academy of Sciences. The research, by Steven D. Douglas, M.D., Jian-Ping Lai, M.D., and Wen-Zhe Ho, M.D., was carried out in human cell cultures.

The compound, CP-96,345, binds to receptors on the surface of monocyte-derived macrophages (MDM), which are immune system cells. These macrophages play an important role in HIV infection because they are a reservoir for the virus. HIV infection remains latent in these cells even while the anti-HIV drug cocktail, highly active antitretroviral therapy, controls the active infection. If the drug cocktail is halted, HIV infection surges back.

"This compound is potentially a very powerful therapy because it may close the door to the virus," said Dr. Douglas, the chief of Immunology at Children’s Hospital and lead author of the article. CP-96,345 interrupts the process by which particular strains of HIV, the R5 strains, enter macrophages through receptors on the macrophage’s cell surface. Many AIDS researchers are targeting those specific receptors, CCR5 receptors, as a way to block HIV infection in its early stages.

Crucial to the action of CP-96,345 is a naturally produced protein called substance P. First discovered in 1930, substance P is a neurotransmitter, a chemical that carries signals within the brain and elsewhere in the nervous system. Known to be an active transmitter of pain signals, substance P also plays an important role, still under investigation, in the immune system. In 1997, Drs. Douglas, Ho and Lai showed that macrophages and other immune system cells produce substance P. Their other studies found that increased levels of substance P were associated with higher levels of stress and anxiety. "Substance P provides a method by which the central nervous system interacts with the immune system," said Dr. Douglas.

The Children’s Hospital team previously showed that substance P raised HIV levels in macrophage cell cultures. Therefore, they designed the current HIV experiment using a substance P antagonist – a chemical that interferes with substance P and its interaction with its receptor. That antagonist, CP-96,345, blocks the binding between substance P and receptors for substance P on the surface of MDMs. Still to be explained is how the interaction between substance P and its receptor on the macrophages affects the CCR5 receptor that allows HIV to infect those cells.

The researchers will continue to study the immunological activities of substance P and its corresponding antagonists. Because substance P is found in both the immune system and the nervous system, one future area of research is to determine whether CP-96,345 might block AIDS-induced dementia and other neurological damage caused by HIV.

Founded in 1855 as the nation's first pediatric hospital, The Children’s Hospital of Philadelphia is ranked today as the best pediatric hospital in the nation by a comprehensive Child Magazine survey. Its pediatric research program is among the largest in the country, ranking second in National Institutes of Health funding.