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

AI Article Synopsis

  • Tissue macrophages, which originate from blood monocytes, support HIV-1 replication except those found in the intestines, which are resistant to the virus due to their unique microenvironment.
  • Researchers used intestinal extracellular matrix (stroma)-conditioned media to analyze how exposure affects monocytes' ability to become macrophages, finding that it inhibited the up-regulation of HIV-1 receptors and blocked viral replication.
  • The study revealed that the resistance of intestinal macrophages to HIV-1 is not solely due to lower receptor expression but involves stromal TGF-β, which reduces NF-κB activation, further preventing productive viral replication.

Article 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.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3102716PMC
http://dx.doi.org/10.1371/journal.ppat.1002060DOI Listing

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