title: Stromal down-regulation of macrophage CD4/CCR5 expression and NF-κB activation mediates HIV-1 non-permissiveness in intestinal macrophages.
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.
authors.affiliation: Department of Medicine (Gastroenterology), University of Alabama at Birmingham, Birmingham, Alabama, United Sates of America.
authors.forename: Ruizhong
authors.initials: R
authors.lastname: Shen
authors.forename: Gang
authors.initials: G
authors.lastname: Meng
authors.forename: Christina
authors.initials: C
authors.lastname: Ochsenbauer
authors.forename: Paul R
authors.initials: PR
authors.lastname: Clapham
authors.forename: Jayleen
authors.initials: J
authors.lastname: Grams
authors.forename: Lea
authors.initials: L
authors.lastname: Novak
authors.forename: John C
authors.initials: JC
authors.lastname: Kappes
authors.forename: Lesley E
authors.initials: LE
authors.lastname: Smythies
authors.forename: Phillip D
authors.initials: PD
authors.lastname: Smith
mesh_terms: D015704:CD4 Antigens / Q000378:metabolism*; D002478:Cells, Cultured; D017077:Culture Media, Conditioned / Q000494:pharmacology; D015536:Down-Regulation / Q000502:physiology*; D015497:HIV-1 / Q000302:isolation & purification / Q000472:pathogenicity / Q000502:physiology*; D006801:Humans; D007413:Intestinal Mucosa / Q000821:virology*; D008264:Macrophages / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism*; D019713:Receptors, CCR5 / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D016212:Transforming Growth Factor beta / Q000494:pharmacology; D014779:Virus Replication / Q000187:drug effects / Q000502:physiology
chemical_list: D015704:CD4 Antigens; D017077:Culture Media, Conditioned; D016328:NF-kappa B; D019713:Receptors, CCR5; D016212:Transforming Growth Factor beta