期刊
PLOS PATHOGENS
卷 7, 期 5, 页码 -出版社
PUBLIC LIBRARY SCIENCE
DOI: 10.1371/journal.ppat.1002060
关键词
-
资金
- National Institutes of Health [DK-74033, DK-47322, DK-54495, DK-84063, AI-83027, AI-83539, DK-61297, RR-20136]
- University of Alabama at Birmingham Mucosal HIV and Immunobiology Center [DK-64400]
- Center for HIV/AIDS Vaccine Immunology [AI-67854]
- Center for AIDS Research Virology and Flow Cytometry Cores [AI-27767]
- Research Service of the Veterans Administration
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-beta in S-CM and recombinant TGF-beta studies showed that stromal TGF-beta inhibited macrophage nuclear translocation of NF-kappa B 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-kappa B activation.
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