July 11, 2002. Copyright 2002. Graphic News. All rights reserved.

New drugs that lock the door on HIV

LONDON, July 11, Graphic News: A designer protein that stops the AIDS virus from breaking and entering is the most clinically advanced weapon in the arsenal against the human immunodeficiency virus (HIV), researchers said at the XIV International AIDS Conference (IAC) in Barcelona, Spain.

Data collected from a survey of more than 600 patients in two internationally conducted Phase III trials suggest that a new class of anti-AIDS drugs -- known as fusion inhibitors -- can drastically reduce HIV infection with little or no impact on quality of life.

The most advanced fusion inhibitors are T-20 and T-1249, made by Trimeris Inc., and developed in partnership with Hoffman-LaRoche. T-20 is a 36-amino acid synthetic peptide which blocks infection by inhibiting viral fusion with host cells. The drug targets an HIV protein called gp41, a key part of the spring-loaded mechanism that the virus uses to break into cells.

HIV replicates by hijacking white blood cells, inserting its viral RNA (its genetic blueprint), and turning the cells into genetic Xerox machines, cranking out copy after copy of the virus. But to break in the virus must get close enough to a lymphocyteÕs protective plasma membrane to make contact with it. 

The cell membrane is constructed of a core of water-insoluble, or hydrophobic (literally, water-hating) lipid sandwiched between two sheets of densely packed, electrically charged hydrophilic (ie, water-loving, or soluble) chemical groups. In addition, the outward surface of the membrane is covered with projecting carbohydrate chains and coated with a film of tightly bound water. As a consequence, most viruses making incidental contact with a lymphocyte donÕt breach these protective barriers and actually touch the membrane itself. 

HIV, however, uses a complex series of chemical tools to gain entry. Initially an HIV glychoprotein, gp120, attaches to CD4 receptors standing out from the lymphocyteÕs surface. The gp41 protein then springs out and ÒharpoonsÓ the cell before snapping back to form a Òhairpin-likeÓ mechanism which clasps the membrane. This enables the viral and the cell membranes to fuse.

Once injected, T-20 mimicks this gp41 protein resulting in a botched formation of the hairpin. Because the virus cannot fuse to the cell it cannot inject its genes and HIV infection stops.

Unlike currently-approved anti-HIV drugs -- reverse transcriptase and protease inhibitors which work inside a cell -- T-20 functions on the outside of a cell. By remaining outside and blocking HIV before it gains entry to the cell, fusion inhibitors are less likely to interact negatively with other drugs or interfere with the bodyÕs immune system. This could be a major advantage as it is more likely to decrease side effects, minimize drug-drug interactions, and simplify dosing. 
/ENDS

Sources: Trimeris Inc., Hoffmann-LaRoche, ÒEntry and Fusion InhibitorsÓ by Professor Joseph J. Eron and Dr. Christine M. Hogan