Stromal Down-Regulation of Macrophage CD4/CCR5 Expression and NF-κB Activation Mediates HIV-1 Non-Permissiveness in Intestinal Macrophages

PLoS Pathogens

Phillip D. Smith¹  Ruizhong Shen¹  John C. Kappes²  Christina Ochsenbauer²  Lea Novak³  Jayleen Grams⁴  Gang Meng⁵  Paul R. Clapham⁶  Lesley E. Smythies⁷ 

[1] Department of Medicine (Gastroenterology), University of Alabama at Birmingham, Birmingham, Alabama, United Sates of America;Department of Medicine (Hematology/Oncology), University of Alabama at Birmingham, Birmingham, Alabama, United States of America;Department of Pathology, University of Alabama at Birmingham, Birmingham, Alabama, United States of America;Department of Surgery (Gastrointestinal), University of Alabama at Birmingham, Birmingham, Alabama, United States of America;Lutheran Family Health Centers, Brooklyn, New York, United States of America;Program in Molecular Medicine and Microbiology, University of Massachusetts, Worcester, Massachusetts, United States of America;VA Medical Center, Birmingham, Alabama, United States of America

关键词: Macrophages;    HIV-1;    Gastrointestinal tract;    Monocytes;    Transcription factors;    Viral replication;    Blood;    Cell differentiation;   

DOI  :  10.1371/journal.ppat.1002060

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

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.

【 授权许可】

CC BY