Chemokine Receptors: Keys to AIDS Pathogenesis?

This major advance followed closely on the heels of the discovery that an activity in lymphocyte supernatants that inhibited HIV replication consisted of three chemo-of macrophage-tropic, but not T cell line–tropic, strains of HIV-1 (Cocchi et al., 1995). Together, these findings set the stage for the demonstration that CCR5, the receptor for the three ␤-chemokines, is the major cofactor Only two years ago, the rapidly expanding families of required for entry of macrophage-tropic strains of HIV-1 chemokines and of their seven-transmembrane G pro-into CD4 ϩ cells (for review, see Weiss and Clapham, tein–coupled receptors (GPCRs) occupied an important, 1996, and references therein). Although other members but not widely recognized, area of biology (reviewed in of this GPCR family have also been shown to shepherd Premack and Schall, 1996). The discoveries that chemo-in various strains of virus, CCR5 and/or CXCR4 remain kines can block HIV replication and that their receptors the receptors used by all known strains of HIV-1. The have essential functions in fusion of HIV to target cells current nomenclature for receptor tropism is R5 (for propelled this field into the limelight, and raised expecta-CCR5-tropic virus), X4 (for CXCR4-tropic virus), and tions that chemokines might hold the key to understand-R5X4 for dual-tropic virus. The expression of CCR5 on ing HIV-mediated pathogenesis, both in the immune sys-macrophages and primary T cells, but not on trans-tem and the central nervous system. Although this formed T cell lines, explains the tropism of most R5 promise has yet to be fulfilled, much has been learned viruses (Figure 1). The reason why X4 viruses replicate since the early exciting findings, and it is now possible in primary and transformed T cells, but not in monocytes to formulate questions with considerably greater clarity. and macrophages, is less clear, because all of these This review will focus on some recent advances and on cells express CXCR4 (Figure 1). It is possible that viral outstanding questions regarding the role of chemokine entry into macrophages is intact, but that replication is receptor family members in the primate lentiviral replica-blocked due to the inability of CXCR4 to transmit a tion cycle and in pathogenesis. requisite signal. Alternatively, entry may fail because of Chemokine Receptors as Determinants cell type–specific restrictions in conformation of CXCR4 of Viral Tropism or in its ability to associate with other proteins. This is The discovery that CD4 is a receptor for HIV and inter-a particularly …