Chemokine receptors--the next therapeutic target for HIV?

To date, the available therapies for the treatment of HIV infection are targeted against proteins encoded by the virus itself. Thus, combination drug therapies for HIV with reverse transciptase and protease inhibitors have resulted in spectacular reductions of viraemia, often leading to a remarkable improvement in symptoms and recovery from disease in infected people. There is still however, a great need for improved therapies since many patients are unable to take these drugs, either for reasons of intolerance, strain resistance, complexity of regimen or prohibitive cost. Multiple therapies aimed at different events in the HIV life cycle will ensure switching of treatments to combat resistant viruses, and also allow treatment flexibility if patients are unable to tolerate particular therapies. One event that could provide a key to reducing or even eliminating viral infection would be to prevent the virus from entering the host cell. Intense efforts are now underway to produce drugs that target chemokine receptors, one of the essential components for HIV cell entry. HIV needs two receptors on the host cell surface for efficient attachment and infection. The first is CD4 and the second, identified in 1996, is a member of the family of chemokine receptors, members of the G-protein coupled 7TM superfamily, which are involved in the trafficking of leukocytes in immune surveillance and inflammation. Many small, orally bioavailable molecules that block various 7TM receptors are used to treat a panoply of diseases including ulcers, allergies, migraines, and schizophrenia. These molecules are the cornerstone of the pharmaceutical industry's contribution to the fight against so many diseases. Small molecule inhibitors of the HIV-coreceptors are now entering the first stages of clinical trials as new therapeutics for the fight against AIDS.