The unexpected encounter between the fields of HIV and
chemokines has opened new perspectives for understanding the mechanisms of
AIDS pathogenesis, as well as for the development of effective
therapies and
vaccines. Selected
chemokines act as potent natural inhibitors of
HIV infection, as they bind and downmodulate
chemokine receptors that serve as critical coreceptors for HIV to gain access into cells. The differential usage of the two major HIV coreceptors, CCR5 and CXCR4, determines the biological diversity among HIV variants. Most primary HIV strains use CCR5 as a coreceptor and thereby are sensitive to inhibition by the CCR5-ligand
chemokines,
RANTES,
MIP-1alpha and
MIP-1beta. The high level of expression of these proinflammatory
chemokines in HIV-infected secondary lymphoid tissues may help to explain the inherently slow course of HIV disease. The crucial role played by CCR5 in the physiology of
HIV infection is further attested by the near-complete resistance to
HIV infection in people carrying a homozygous 32 bp deletion within the CCR5 gene (CCR5-delta32). A smaller proportion of HIV isolates, commonly emerging in concomitance with the
clinical progression toward
AIDS, uses CXCR4 as a coreceptor and is inhibited by the CXCR4
ligand, SDF-1. The high level of expresion of SDF-1 in the genital mucosa may help to explain the inefficient transmission of CXCR4-tropic HIV. Although
chemokines or derivative-molecules could be exploited as therapeutic agents against HIV, the risk of inducing inflammatory side-effects or of interfering with the physiology of the homeostatic
chemokine system represents a potential limitation. However, the ability of
chemokines to block
HIV infection can be uncoupled from their receptor-mediated signaling activity, thus providing a theoretical foundation for the rational design of safe and effective
chemokine receptor inhibitors.