CCAAT/enhancer binding protein beta is a major mediator of inflammation and viral replication in the gastrointestinal tract of simian immunodeficiency virus-infected rhesus macaques.
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 beta (C/EBPbeta) 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/EBPbeta 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, CEBPbeta expression was localized predominantly to macrophages and occasionally lymphocytes. Chromatin immunoprecipitation assays confirmed the binding of C/EBPbeta 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/EBPbeta 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.
Division of Comparative Pathology, Tulane National Primate Research Center, Covington, Louisiana 70433, USA.
Mahesh
M
Mohan
Pyone P
PP
Aye
Juan T
JT
Borda
Xavier
X
Alvarez
Andrew A
AA
Lackner
D000818:Animals; D015153:Blotting, Western; D022782:CCAAT-Enhancer-Binding Protein-beta / Q000378:metabolism*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D003967:Diarrhea / Q000821:virology; D015870:Gene Expression; D047468:Immunoprecipitation; D007249:Inflammation / Q000276:immunology / Q000473:pathology / Q000821:virology*; D007413:Intestinal Mucosa / Q000378:metabolism / Q000473:pathology / Q000821:virology*; D008253:Macaca mulatta; D018613:Microscopy, Confocal; D012333:RNA, Messenger / Q000032:analysis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016097:Simian Acquired Immunodeficiency Syndrome / Q000276:immunology* / Q000378:metabolism / Q000821:virology*; D015302:Simian Immunodeficiency Virus / Q000502:physiology; D019562:Viral Load; D014779:Virus Replication / Q000502:physiology*
D022782:CCAAT-Enhancer-Binding Protein-beta; D012333:RNA, Messenger