Abstract
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.
Highlights
Macrophages play crucial roles in the establishment, pathogenesis and latency of human immunodeficiency virus-1 (HIV-1) infection [1,2,3] through their ability to support viral replication [4,5], transmit virus [6] and act as a viral reservoir [6,7,8,9]
We report that intestinal stroma potently blocked up-regulation of HIV-1 receptor/coreceptor CD4 and CCR5 expression during monocyte differentiation into macrophages and macrophage nuclear translocation of nuclear factor kappa B (NF-kB), which is a critical requirement for HIV-1 transcription
Intestinal macrophages and blood monocytes were isolated from the same donors, purified and analyzed for expression of the HIV-1 primary receptor CD4 and the coreceptors CCR5 and CXCR4
Summary
Macrophages play crucial roles in the establishment, pathogenesis and latency of human immunodeficiency virus-1 (HIV-1) infection [1,2,3] through their ability to support viral replication [4,5], transmit virus [6] and act as a viral reservoir [6,7,8,9]. The unique non-permissiveness of intestinal macrophages to HIV-1 stands in marked contrast to the ability of intestinal CD4+ T cells to support productive viral infection and undergo early, rapid and profound depletion during primary HIV1 and SIV infection [19,20,21,22,23,24,25,26] After their recruitment into the lamina propria, pro-inflammatory blood monocytes differentiate into non-inflammatory intestinal macrophages through stromal transforming growth factor b (TGF-b)-mediated Smad-induced IkBa and nuclear factor kappa B (NF-kB) inactivation, as we recently reported [27,28]. Since CCR5 expression correlates directly with the differentiation of monocytes into macrophages [32,33,34], the reduced expression of CCR5 on intestinal macrophages raises the possibility that the non-
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