HIV coreceptors: from discovery and designation to new paradigms and promise.

Just over a decade ago, the specific chemokine receptors CXCR4 and CCR5 were identified as the essential coreceptors that function along with CD4 to enable human immunodeficiency virus (HIV) entry into target cells. The coreceptor discoveries immediately provided a molecular explanation for the distinct tropisms of different HIV-1 isolates for different CD4-positive target cell types, and revealed fundamentally new insights into host and viral factors influencing HIV transmission and disease. The sequential 2-step mechanism by which the HIV envelope glycoprotein (Env) interacts first with CD4, then with coreceptor, revealed a major mechanism by which conserved Env epitopes are protected from antibody-mediated neutralization. The Env-coreceptor interaction has become a major target for the development of novel antiviral strategies to treat and prevent HIV infection.