Antigenically distinct conformations of CXCR4

The major human immunodeficiency virus type 1 (HIV-1) coreceptors are the c hemokine receptors CCR5 and CXCR4. The patterns of expression of the major coreceptors and their use by HIV-1 strains largely explain viral tropism at the level of entry. However, while virus infection is dependent upon the p resence of CD4 and an appropriate coreceptor, it can be influenced by a num ber of factors, including receptor concentration, affinity between envelope gp120 and receptors, and potentially receptor conformation. Indeed, seven- transmembrane domain receptors, such as CCR5, can exhibit conformational he terogeneity, although the significance for virus infection is uncertain. Us ing a panel of monoclonal antibodies (MAbs) to CXCR4, we found that CXCR4 o n both primary and transformed T cells as well as on primary B cells exhibi ted considerable conformational heterogeneity. The conformational heterogen eity of CXCR4 explains the cell-type-dependent ability of CXCR4 antibodies to block chemotaxis to stromal cell-derived factor 1 alpha and to inhibit H IV-1 infection. In addition, the MAb most commonly used to study CXCR4 expr ession, 12G5, recognizes only a subpopulation of CXCR4 molecules on all pri mary cell types analyzed. As a result, CXCR4 concentrations on these import ant cell types have been underestimated to date. Finally, while the factors responsible for altering CXCR4 conformation are not known, we found that t hey do not involve CXCR4 glycosylation, sulfation of the N-terminal domain of CXCR4, or pertussis toxin-sensitive G-protein coupling. The fact that th is important HIV-1 coreceptor exists in multiple conformations could have i mplications for viral entry and for the development of receptor antagonists .