Important note: Information in this article was accurate in May 2000. The state of the art may have changed since the publication date.
When invading bacteria, viruses and fungi need to be brought under control, the immune system directs T- and other cells to the location of the infection by producing a chemical trail. One group of chemicals used to produce this trail are called chemokines. These chemicals also appear to influence the movement of the immune system's cells around the body, whether an infection is present or not.
To make use of chemokines, cells have receptors called chemokine receptors. Researchers have found that HIV attaches itself to certain chemokine receptors and is then able to enter and infect a cell. By covering up or blocking the chemokine receptor(s), researchers hope to prevent HIV from infecting cells.
Although there are many chemokines and associated receptors, research efforts have focused on blocking one particular receptor called CXCR4 or simply X4. Chemokine blockers are a new group of compounds that may prove useful against HIV. One chemokine blocker that is being tested as a possible therapy is AMD-3100. We report preliminary results from a study of this drug later in this issue. First, it is important that we raise a number of important issues related to this group of compounds.
As chemokines are used to direct the movement of lymphocytes, blocking the receptors for these chemical signals could affect the ability of these cells to travel. This is particularly important because 98% of T-cells are found in the lymph nodes and tissues and not in the blood. Most HIV is also found in lymph nodes and tissues. Chemokine blockers have the potential to confuse T-cells and prevent them from migrating to parts of the body where they are needed to fight HIV. Similarly, chemokine blockers could affect the immune system's ability to fight other infections.
Brain cells have receptors for chemokines so it is not clear what effect blocking these receptors will have on the nervous systems of people with HIV/AIDS.
AMD-3100 is easily absorbed by fat and its effect on human fat cells has not yet been described in a published study.
Results from a short study on the safety of AMD-3100 have been interesting. The trial enrolled 12 healthy subjects, most of whom received only one dose of AMD-3100 given either intravenously, orally or injected under the skin (subcutaneously).
The researchers found that levels of white blood cells rose temporarily, by as many as three times their pre-study level in some cases. Use of chemokine blockers may, therefore, make it difficult to correctly interpret the results of lab tests used to measure white and other blood cells.
At a dose of 40 micrograms per kilogram of body weight, three of three subjects given this dose developed gastrointestinal symptoms, including the following:
Injecting AMD-3100 under the skin resulted in levels in the blood sufficient to have anti-HIV activity. Less than 2% of AMD-3100 is absorbed when taken orally.
AMD-3100 is being tested in the Unites States in HIV-positive people. The drug is made by AnorMED Inc., in Langley, British Columbia.
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