The discovery that the HIV-1 coreceptors have natural ligands and signaling functions suggested immediate therapeutic possibilities (a list of chemokine-related inhibitory strategies is presented in Table II and discussed throughout the text). The chemokine receptors are normally in-
Chemokine Receptor Inhibitors and Strategies
Chernokine ligands Viral chemokines Chemokine variants Chernokine derivatives HIV suppression by chemokines Receptor downregulation Receptor cross-regulation Gene therapy delivery Intracellular receptor interference Selective cell targeting Small-molecule inhibitors
AOP-RANTES, Met-RANTES MCPl
Reverse pseudotyped vectors Antisense, intrakine Zidovudine, didanosine T22, AMD3100, ALX40-4C
volved in the chemoattractive localization of cells by transducing a signal upon binding a chemokine ligand (for review see Premack and Schall45). As such, nearly all cells of the hematopoietic lineage express chemokine receptors of some sort, although chemokine receptors are also found on a surprisingly large number of other primary cell types and cell lines. Binding of a chemokine ligand to the extracellular loops of its receptor not only induces a signal within the cell, but can also prevent HIV-1 utilization of the receptor.20-21'23-24 Chemokines directed to fusogenic chemokine receptors such as CXCR4, CCR5, CCR3, and CCR8 inhibit use oftheir cognate receptors by HIV-1, although the degree of inhibition can vary tremendously depending on the Env protein.46 The mechanism of inhibition by chemokine ligands largely involves direct steric hindrance of the Env protein, but downregulation of the receptor caused by ligand-induced signaling may also contribute to entry inhibition.47 In addition, indirect signaling effects by other chemokines, such as MCPl or MDC, may also play a role in regulating the availability of the chemokine receptor to Env.4849
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