HIV-1 ENVELOPE GP41 IS A POTENT INHIBITOR OF CHEMOATTRACTANT RECEPTOREXPRESSION AND FUNCTION IN MONOCYTES

HIV-1 uses CD4 and chemokine receptors as cofactors for cellular entry . The viral envelope transmembrane protein gp41 is thought to particip ate in viral fusion with CD4(+) cells. We investigated whether gp41 in teracts with chemokine receptors on human monocytes by testing its eff ect on the capacity of cells to respond to chemokine stimulation. Mono cytes preincubated with gp41 of the MN strain showed markedly reduced binding, calcium mobilization, and chemotaxis in response to a variety of chemokines as well as to the bacterial peptide fMLP. This generali zed inhibition of monocyte activation by chemoattractants required the presence of CD3, since the effect of gp41 was only observed in CD4(+) monocytes and in HEK293 cells cotransfected with chemokine receptors and an intact CD3, but not a CD4 lacking its cytoplasmic domain. Confo cal microscopy showed that gp41 caused internalization of CXCR4 in HEK 293 cells provided they were also cotransfected with intact CD4. In ad dition, pretreatment of monocytes with protein kinase C inhibitors par tially reversed the inhibitory effect of gp41. Thus, gp41, which had n ot previously been implicated as interacting with HIV-1 fusion cofacto rs, downregulates chemoattractant receptors on monocytes by a CD4-depe ndent pathway.