Published online before print June 5, 2008

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Copyright © 2008 American Society for Investigative Pathology
American Journal of Pathology, doi:10.2353/ajpath.2008.080108

Accepted for publication April 8, 2008.

Article

CCAAT/Enhancer Binding Protein Is a Major Mediator of Inflammation and Viral Replication in the Gastrointestinal Tract of Simian Immunodeficiency Virus-Infected Rhesus Macaques

From the Division of Comparative Pathology, Tulane National Primate Research Center, Covington, Louisiana

^@ To whom correspondence should be addressed. E-mail: alackner{at}tulane.edu.

	Abstract

The gastrointestinal tract (GIT) is a major target of infection with human immunodeficiency virus (HIV) and simian immunodeficiency virus (SIV). Chronic GIT disease and inflammation are common sequelae to HIV/SIV infection. Nonetheless, the molecular mechanisms that cause and maintain GIT dysfunction remain unclear. We investigated the contribution of CCAAT/enhancer-binding protein (C/EBP) to GIT disease and viral replication in jejunum and colon collected at necropsy from 12 SIV-infected (group 1), or 10 uninfected macaques with chronic diarrhea (group 2), and 9 uninfected control macaques (group 3). All group 1 and 2 macaques had chronic diarrhea, wasting, and colitis, but group 1 animals had more severe lesions in the jejunum. C/EBP gene expression increased significantly in colon of groups 1 and 2 and in jejunum of only group 1 macaques compared with controls. In group 1 animals, CEBP expression was localized predominantly to macrophages and occasionally lymphocytes. Chromatin immunoprecipitation assays confirmed the binding of C/EBP and p65 to the SIV long terminal repeat region in colonic lamina propria cells, suggesting a mechanistic link between inflammation and activation of viral replication in vivo. This is the first in vivo study describing the transcriptional changes and immunophenotypic localization of C/EBP in the GIT of SIV-infected macaques. More importantly, these data provide a molecular mechanism for persistent inflammation and immune activation leading to increased SIV burden and GIT pathology in SIV-infected macaques and perhaps HIV-infected individuals.