Stromal down-regulation of macrophage CD4/CCR5 expression and NF-κB activation mediates HIV-1 non-permissiveness in intestinal macrophages

Tissue macrophages are derived exclusively from blood monocytes,which as monocyte-derived macrophages support hiv-1 replication. however,among human tissue macrophages only intestinal macrophages are non-permissive to hiv-1,suggesting that the unique microenvironment in human intestinal mucosa renders lamina propria macrophages non-permissive to hiv-1. we investigated this hypothesis using blood monocytes and intestinal extracellular matrix (stroma)-conditioned media (s-cm) to model the exposure of newly recruited monocytes and resident macrophages to lamina propria stroma,where the cells take up residence in the intestinal mucosa. exposure of monocytes to s-cm blocked up-regulation of cd4 and ccr5 expression during monocyte differentiation into macrophages and inhibited productive hiv-1 infection in differentiated macrophages. importantly,exposure of monocyte-derived macrophages simultaneously to s-cm and hiv-1 also inhibited viral replication,and sorted cd4+ intestinal macrophages,a proportion of which expressed ccr5+,did not support hiv-1 replication,indicating that the non-permissiveness to hiv-1 was not due to reduced receptor expression alone. consistent with this conclusion,s-cm also potently inhibited replication of hiv-1 pseudotyped with vesicular stomatitis virus glycoprotein,which provides cd4/ccr5-independent entry. neutralization of tgf-β in s-cm and recombinant tgf-β studies showed that stromal tgf-β inhibited macrophage nuclear translocation of nf-κb and hiv-1 replication. thus,the profound inability of intestinal macrophages to support productive hiv-1 infection is likely the consequence of microenvironmental down-regulation of macrophage hiv-1 receptor/coreceptor expression and nf-κb activation.