BALTIMORE--Following the battlefield tactic of divide and conquer (in this case, dividing a molecule into two fragments), University of Maryland Baltimore County (UMBC) researchers have determined the three-dimensional structure of a key part of the HIV-1 p24 capsid protein (see illustration on page 1).
This protein forms a shell within the AIDS virus that encapsulates the virus' RNA and some enzymes vital to its ability to infect cells and replicate.
"This new information suggests potential new targets for drug development and provides new insights into the process of HIV replication," Jack Killen, MD, director of the division of AIDS at the National Institute of Allergy and Infectious Diseases, said in a statement.
The HIV-1 capsid (CA) fragment contains within it the binding site for cyclophilin A, a protein that is found in most blood cells and is the target for the immunosuppressant cyclosporin. Earlier work by Columbia University researchers demonstrated that HIV's capsid protein must bind cyclophilin A for HIV-1 to infect cells.
"We now have a detailed picture of the cyclophilin A binding site, and that information should be crucial to scientists who are designing antiviral agents based on inhibiting cyclophilin A's interaction with HIV-1," Michael F. Summers, PhD, professor of chemistry at UMBC and associate investigator at the Howard Hughes Medical Institute, said at a media briefing.
Surprisingly, the HIV-1 CA fragment has a structure unlike any other viral coat protain listed in the Brookhaven National Laboratory database.
The new findings, detailed in Science (273:231-235, 1996), cap a 6-year effort by Dr. Summers to unravel the structure of the HIV-1 capsid protein. HIV contains eight proteins and scientists have now determined the 3D structure of six. He and his coworkers had previously resolved the features of two other HIV-1 structural proteins besides p24--p7 nucleocapsid, a protein inside the viral core, and the p17 matrix protein that lies between the core and the viral membrane.