TreatmentUpdate83 - Vol. 9, No. 9 - pp. 2; November 1997
Sean Hosein

Chemokines are molecules that cells of the immune system use to send signals to each other. Generally, by releasing chemokines cells can form a chemical trail allowing other cells to follow and gather at sites of infection. Cells have receptors for chemokines which allow them to capture this molecule so that they can receive its message. Now it appears that HIV can also use these chemokine receptors to enter and infect cells. By blocking the chemokine receptor, researchers hope to prevent HIV from infecting cells. The focus of much of the work in progress is to block HIV from entering two types of cells, that is, T cells and macrophages.

Handy inhibitors--off the shelf

There are several strategies that could be used to block chemokine receptors. People could be given massive doses of artificial chemokines but these are not likely to be well absorbed if taken orally. Another is to make mutated chemokines which would also gum up the receptors but these are crude and likely to cause problems. A simpler approach is to make small molecules that can fit into the receptor. A number of drug companies are making such compounds. Taking stock of existing chemicals that might do the trick could get some products into human testing faster. We now look at 3 such "off-the shelf" compounds.

One chemical is called AMD3100. In lab experiments with cells, AMD3100 blocks HIV from entering a chemokine receptor called CXCR4. Another potential treatment is ALX40-4C, which also blocks HIV from entering the same receptor. Finally, the compound T22 also blocks entry of HIV into CXCR4. What all these drugs have in common is that they are not new. They have all been tested in the 1990s in Canada, Europe and Japan in lab experiments that found them to have anti-HIV activity. ALX40-4C was originally developed in Canada as a 'tat-inhibitor'. At that time in the early 1990s no one knew about their effects on chemokine receptors. The next step is to test these and other compounds in monkeys with SIV infection.

REFERENCES:

1. Bagggiolini M and Moser B. Blocking chemokine receptors. Journal of Experimental Medicine 1997;186(8):1189-1191.

2. Shols D, Struyf S, Van Damme J, et al. Inhibition of T-tropic HIV strains by selective antagonization of the chemokine receptor CXCR4. Journal of Experimental Medicine 1997;186(8):1383-1388.

3. Murakami T, Nakajima T, Koyanagi Y, et al. A small molecule CXCR4 inhibitor that blocks T cell line-trophic HIV-1 infection. Journal of Experimental Medicine 1997;186(8):1389-1393.

4. Doranz BJ, Grovit-Ferbas K, Sharron MP, et al. A small-molecule inhibitor directed against the chemokine receptor CXCR4 prevents its use as an HIV-1 co-receptor. Journal of Experimental Medicine 1997;186(8):1395-1400.

971101
CATE8302

Copyright © 1997 - TreatmentUpdate. Reproduced with permission. Reproduction of this article (other than one copy for personal reference) must be cleared through the Editor, The Canadian AIDS Treatment Information Exchange, 555 Richmond St. West, Suite 505, Box 1104, Toronto, ON, M5V 3B1 • Phone: 416-203-7122 • Toll Free: 1-800-263-1638 • Fax: 416-203-8284  http://www.catie.ca