Chemokine receptors: emerging opportunities for new anti-HIV therapies

The chemokine receptors CCR5 and CXCR4 are G-protein coupled receptors (GPCRs) of the immune system and the major co-receptors required for entry of HIV into CD4(+) target cells. CCR5 is critical for both human immunodeficiency virus (HIV) disease transmission and progression, whereas CXCR4 may be very important in late stages of disease. Additional co-receptors have been shown to function under certain conditions in vitro but evidence of supporting roles in HIV disease is currently lacking. The sheer number of co-receptors potentially used by HIV and the complexity of co-receptors usage are major challenges confronting usage of these molecules as drug development targets. Balanced against this, is a long history of success by the pharmaceutical industry in developing small molecule antagonists for many other classes of GPCRs. In this review, we discuss the current state of understanding of the co-receptor-based antiviral agents designed to block viral entry. The therapeutic potential of this field will be judged from future studies on the efficacy of these novel inhibitors in clinical trials. The data so far obtained from a number of studies point to the potential clinical use of this emerging class of therapeutic agents. Here we review current progress in co-receptor-based antiretroviral drug development and discuss the potential advantages and disadvantages of this approach.