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(Journal of Leukocyte Biology. 2006;80:1111-1117.)
© 2006 by Society for Leukocyte Biology

Cytomegalovirus blocks intestinal stroma-induced down-regulation of macrophage HIV-1 infection

Akhil Maheshwari^*, Lesley E. Smythies, Xiaoyun Wu, Lea Novak, Ronald Clements, Devin Eckhoff, Audrey J. Lazenby, William J. Britt^* and Phillip D. Smith^,¶,1

^* Departments of Pediatrics,
Medicine,
Pathology, and
Surgery, University of Alabama at Birmingham, Birmingham, Alabama, USA; and the
^¶ VA Medical Center, Birmingham, Alabama, USA

¹ Correspondence: Department of Medicine (Gastroenterology), University of Alabama at Birmingham (ZRB 633), 703 19th Street South, Birmingham, AL 35294. E-mail: pdsmith{at}uab.edu

ABSTRACT

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-, but preinfection of the cells with CMV reversed this down-regulation, enhancing HIV-1 infection, p24 production, and TNF- release. The ability of CMV to reverse S-CM down-regulation of macrophage HIV-1 infection was blocked by anti-TNF- antibodies and over-ridden by exogenous TNF-. 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- proteins, others contained HIV-1 and TNF- 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- acting in trans to enhance HIV-1 infection.

Key Words: mucosa • intestinal macrophage • extracellular matrix • TNF-

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