Cytomegalovirus blocks intestinal stroma-induced down-regulation of macrophage HIV-1 infection.
Intestinal macrophages, unlike macrophages from other tissues, do not support HIV-1 infection or produce proinflammatory cytokines. In vitro studies suggest this unique, functional phenotype is a result of the exposure of newly recruited blood monocytes to intestinal stromal products. However, in AIDS-related CMV colitis, mucosal macrophages express HIV-1 and proinflammatory cytokines. Therefore, we investigated the mechanism by which CMV confers permissiveness to HIV-1 and cytokine production on intestinal macrophages. We show that intestinal stroma-conditioned media (S-CM) down-regulated monocyte-derived macrophage infection by HIV-1 (pseudotyped with YU2 envelope or vesicular stomatitis virus glycoprotein) and production of TNF-alpha, but preinfection of the cells with CMV reversed this down-regulation, enhancing HIV-1 infection, p24 production, and TNF-alpha release. The ability of CMV to reverse S-CM down-regulation of macrophage HIV-1 infection was blocked by anti-TNF-alpha antibodies and over-ridden by exogenous TNF-alpha. Immunohistochemical analysis of monocyte-derived macrophages exposed to CMV and HIV-1 (YU2 pseudotype) revealed that the cells infrequently contained CMV and HIV-1 viral proteins. In addition, analysis of colon tissue sections from HIV-1-infected patients with CMV colitis showed that some macrophage-like cells contained CMV and TNF-alpha proteins, others contained HIV-1 and TNF-alpha proteins, but cells infrequently contained CMV and HIV-1 proteins. These results indicate that CMV blocks stromal product inhibition of HIV-1 infection in macrophages, and this inhibition is mediated, at least in part, by CMV-induced TNF-alpha acting in trans to enhance HIV-1 infection.
Maheshwari
Akhil
A
Department of Pediatrics, University of Alabama at Birmingham (ZRB 633), 703 19th Street South, Birmingham, AL 35294, USA.
Smythies
Lesley E
LE
Wu
Xiaoyun
X
Novak
Lea
L
Clements
Ronald
R
Eckhoff
Devin
D
Lazenby
Audrey J
AJ
Britt
William J
WJ
Smith
Phillip D
PD
D002478:Cells, Cultured; D017077:Culture Media, Conditioned / Q000494:pharmacology; D003587:Cytomegalovirus / Q000276:immunology*; D015536:Down-Regulation / Q000187:drug effects / Q000276:immunology*; D015658:HIV Infections / Q000276:immunology*; D006801:Humans; D007422:Intestines / Q000166:cytology / Q000276:immunology* / Q000821:virology; D008264:Macrophages / Q000187:drug effects / Q000276:immunology* / Q000821:virology; D017154:Stromal Cells / Q000276:immunology* / Q000821:virology; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
D017077:Culture Media, Conditioned; D014409:Tumor Necrosis Factor-alpha