HIV CORECEPTOR DOWN-REGULATION AS ANTIVIRAL PRINCIPLE - SDF-1-ALPHA-DEPENDENT INTERNALIZATION OF THE CHEMOKINE RECEPTOR CXCR4 CONTRIBUTES TO INHIBITION OF HIV REPLICATION

Ligation of CCR5 by the CC chemokines RANTES, MIP-1 alpha or MIP-1 bet a, and of CXCR4 by the CXC chemokine SDF-1 alpha, profoundly inhibits the replication of HIV strains that use these coreceptors for entry in to CD4(+) T lymphocytes. The mechanism of entry inhibition is not know n. We found a rapid and extensive downregulation of CXCR4 by SDF-1 alp ha and of CCR5 by RANTES or the antagonist RANTES(9-68). Confocal lase r scanning microscopy showed that CCR5 and CXCR4, after binding to the ir Ligands, are internalized into vesicles that qualify as early endos omes as indicated by colocalization with transferrin receptors. Intern alization was not affected by treatment with Bordetella pertussis toxi n, showing that it is independent of signaling via G(i)-proteins. Remo val of SDF-1 alpha led to rapid, but incomplete surface reexpression o f CXCR4, a process that was not inhibited by cycloheximide, suggesting that the coreceptor is recycling from the internalization pool. Delet ion of the COOH-terminal, cytoplasmic domain of CXCR4 did not affect H IV entry, but prevented SDF-1 alpha-induced receptor downregulation an d decreased the potency of SDF-1 alpha as inhibitor of HIV replication . Our results indicate that the ability of the coreceptor to internali ze is not required for HIV entry, but contributes to the HIV suppressi ve effect of CXC and CC chemokines.