This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. The Gastrointestinal (GI) tract is critical to AIDS pathogenesis as it is the primary site for viral transmission and a major site of viral replication and CD4+ T cell destruction. Consequently GI disease, a major complication of HIV/SIV infection can facilitate translocation of luminal bacterial products causing localized/systemic immune activation leading to AIDS progression. To better understand the molecular mechanisms underlying GI disease we analyzed global gene expression profiles sequentially in the intestine of the same animals prior to and at 21 and 90d post SIV infection (PI). We maximized information gathering by obtaining sequential intestinal resections and examining distinct mucosal components (intraepithelial lymphocytes, lamina propria lymphocytes [LPL], epithelium and fibrovascular stroma) separately. Here we report data pertaining to the LPL. A significant increase (?1.7-fold) in immune defense/inflammation, cell adhesion/migration, cell signaling, and cell division/differentiation genes were observed at 21 and 90d PI. Genes associated with the JAK-STAT pathway (IL21, IL12R, STAT5A, IL10, SOCS1) and T-cell activation (NFATc1) were notably upregulated at 21d PI. Markedly downregulated genes at 21d PI included IL17D/IL27 and IL28B/IFN?3, activation induced cytidine deaminase and approximately 43 genes regulating oxidative phosphorylation, a critical metabolic shift associated with T-cell activation. The 90d transcriptome revealed further augmentation of inflammation (CXCL11, chitinase-1, JNK3), immune activation (semaphorin7A), B-cell dysfunction (CD70), intestinal microbial translocation (LBP) and mitochondrial antiviral signaling (NLRX1) genes. Reduced expression of CD28, CD4, CD86, NFATc1, TLR8, IL8 and CCL18 at 90d PI suggests further deterioration of immune cell function. The transcriptional signatures provide significant new details on the molecular pathology of HIV/SIV induced GI disease and represent promising targets for future therapy.

Agency
National Institute of Health (NIH)
Institute
National Center for Research Resources (NCRR)
Type
Primate Research Center Grants (P51)
Project #
5P51RR000164-50
Application #
8358171
Study Section
Special Emphasis Panel (ZRR1-CM-8 (01))
Project Start
2011-05-01
Project End
2012-04-30
Budget Start
2011-05-01
Budget End
2012-04-30
Support Year
50
Fiscal Year
2011
Total Cost
$57,750
Indirect Cost
Name
Tulane University
Department
Obstetrics & Gynecology
Type
Schools of Medicine
DUNS #
053785812
City
New Orleans
State
LA
Country
United States
Zip Code
70118
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