Science 341, 1387–1390 (2013)

Credit: BEILI WU

The HIV-1 envelope glycoprotein gp120 acts as a receptor for binding immune cells that express the chemokine receptors CCR5 and/or CXCR4, which act as gp120 co-receptors for viral entry into host cells. Being able to bind either CCR5 or CXCR4 or both is a result of HIV tropism, the virus's ability to evolve its co-receptor specificity, driven primarily by gp120, to infect a greater variety of cells. To better to understand HIV tropism, Tan et al. first solved the structure of CCR5 with maraviroc, a CCR5 inverse agonist that allosterically stabilizes the receptor in an inactive conformation. Confirming this mechanism of action, the CCR5-maraviroc structure shows specific residues in conformations similar to those observed in other inactive structures. The maraviroc-binding site is different from a chemokine ligand-binding site in the 7-transmembrane region, which helps to explain its allosteric action, whereas some specific maraviroc interactions within CCR5 helices I-III and V-VII are supported by previous SAR data and mutagenesis studies. The authors next built models of the interaction between the co-receptors and each of two variable loop (V3) region variants of gp120, one specific for CCR5 and one for CXCR4. These structural studies, combined with sequence analysis of charge distribution of the two gp120 V3 regions, suggest that different charge distributions and steric hindrances in the chemokine receptor-binding pockets could be important in HIV tropism.