HIV-1 ENVELOPE GP120 INHIBITS THE MONOCYTE RESPONSE TO CHEMOKINES THROUGH CD4 SIGNAL-DEPENDENT CHEMOKINE RECEPTOR DOWN-REGULATION

Since HIV-1 infection results in severe immunosuppression, and the env elope protein gp120 has been reported to interact with some of the che mokine receptors on human T lymphocytes, we postulated that gp120 may also affect monocyte activation by a variety of chemokines. This study shows that human peripheral blood monocytes when preincubated with gp 120 either purified from laboratory-adapted strains or as recombinant proteins exhibited markedly reduced binding, calcium mobilization, and chemotactic response to chemokines. The gp-120-pretreated monocytes a lso showed a decreased response to FMLP, This broad inhibition of mono cyte activation by chemoattractants required interaction of gp120 with CD4, since the effect of gp120 was only observed in CD4(+) monocytes and in HEK 293 cells only if cotransfected with both chemokine recepto rs and an intact CD4, but not a CD4 lacking its cytoplasmic domain. An ti-CD4 mAbs mimicked the effect of gp120, and both anti-CD4 Ab and gp1 20 caused internalization of CXCR4 in HEK 293 cells provided they also expressed CH4. Staurosporine blocked the inhibitory effect of gp120 o n monocytes, suggesting that cellular signaling was required for gp120 to inhibit the response of CD4(+) cells to chemoattractants. Our stud y demonstrates a broad suppressive effect of gp120 on monocyte activat ion by chemoattractants through the downregulation of cell surface rec eptors, Thus, gp120 may be used by HIV-1 to disarm the monocyte respon se to inflammatory stimulation.