Unité de pathogenèse virale moléculaire, Inserm U819, Département de virologie, Institut Pasteur, 28, rue Dr Roux, 75015 Paris, Unité d’immunopathologie du sida, Instituto de Salud Carlos III, Majadahonda, Espagne
Entry of HIV in host cells is a highly specific step in the viral life cycle amenable to therapeutic intervention with reduced risk of toxicity. This review focuses on the development of new drugs targeting HIV coreceptors CXCR4 or CCR5, a major aim of AIDS research. CCR5 is critically involved both in transmission and propagation of HIV infection and this role makes it a foremost target for therapeutic intervention. The new CCR5 antagonists behave as allosteric inhibitors inducing CCR5 conformational changes that prevent binding of CCR5-tropic viral envelope glycoproteins to the coreceptor. This new class of inhibitors is active on large spectrum of CCR5-dependent viruses, are orally administrable and reduce viral load by 1 to 2 orders of magnitude. The hope generated by the availability of these drugs is jeopardized by the emergence of resistant virus and the appearance of genetically unrelated CXCR4-tropic, minor viral populations, present before the onset of the treatment. This problem underlines the necessity of developing drugable CXCR4 inhibitors in a close future, a challenge rendered difficult by the important physiological roles accomplished by this receptor.