Lipopolysaccharide inhibits HIV-1 infection of monocyte-derived macrophages through direct and sustained down-regulation of CC chemokine receptor 5

It is now web established that HIV-1 requires interactions with both CD4 an d a chemokine receptor on the host cell surface for efficient infection. Th e expression of the CCR5 chemokine receptor in human macrophages facilitate s HIV-1 entry into these cells, which are considered important in HIV patho genesis not only as viral reservoirs but also as modulators of altered infl ammatory function in HIV disease and AIDS. LPS, a principal constituent of Gram-negative bacterial cell walls, is a potent stimulator of macrophages a nd has been shown to inhibit HIV infection in this population. We now prese nt evidence that one mechanism by which LPS mediates its inhibitory effect on HIV-1 infection is through a direct and unusually sustained down-regulat ion of cell-surface CCR5 expression. This LPS-mediated down-regulation of C CR5 expression was independent of de novo protein synthesis and differed fr om the rapid turnover of these chemokine receptors observed in response to two natural ligands, macrophage-inflammatory protein-1 alpha and -1 beta. L PS did not act by down-regulating CCR5 mRNA (mRNA levels actually increased slightly after LPS treatment) or by enhancing the degradation of internali zed receptor, Rather, the observed failure of LPS-treated macrophages to ra pidly restore CCR5 expression at the cell-surface appeared to result from a ltered recycling of chemokine receptors, Taken together, our results sugges t a novel pathway of CCR5 recycling in LPS-stimulated human macrophages tha t might be targeted to control HIV-1 infection.