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Discovery of HIV-1 Protein Structure Could Lead to New Therapies

Discovery of HIV-1 Protein Structure Could Lead to New Therapies

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.

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