The gastrointestinal (GI) tract is a major target of HIV/SIV infection and CD4+ T cell depletion. The damage to the mucosal immune system is associated with a variety of GI manifestations collectively called AIDS enteropathy;generally characterized by chronic diarrhea, and wasting. Although our understanding of HIV/SIV enteropathy has greatly improved lately, the recent discovery of microRNAs (miRNAs) has added yet another novel and complex regulator of gene expression with potential roles in the molecular pathogenesis of this disorder. miRNAs are ~21-23 nucleotide noncoding RNAs, highly conserved and suppress gene expression by targeting mRNAs for translational repression or degradation. While miRNA studies are being reported extensively in various types of cancer, and at increasing rates in cardiac, neurological, metabolic and skin diseases, their role in idiopathic GI disorders such as HIV/SIV enteropathy is unknown and yet to be addressed. Preliminary Locked Nucleic Acid-based miRNA microarray profiling of colon tissue from SIV-infected macaques with chronic diarrhea and wasting revealed significant deregulation in the expression of several miRNAs. Based on our strong preliminary evidence, we hypothesize that miRNA expression is deregulated in the GI tract consequent to HIV/SIV infection and that this contributes to disruption of enteric structure and function (AIDS enteropathy). The broad goals of this study are to 1a.) Identify genome wide temporal changes in miRNA expression (microarray and miRNA cloning) in the GI tract in response to SIV infection and determine if expression signatures specific to pathogenic events such as immune activation, inflammation, and epithelial barrier disruption can be identified 1b.) Further corroborate all miRNAs showing differential expression using real-time RT-PCR. 1c.) Determine cellular localization of differentially expressed miRNAs (in situ hybridization/immunofluorescence) in the colon and verify if differences in expression exist between cell types in close proximity 2.) Determine the functional significance of the inflammation associated miR-212 by validating its putative protein targets (mass spectrometry) in the intestinal epithelium and in in vitro cultured primary intestinal macrophages. Understanding the role of miRNAs and their putative target genes/proteins will provide important insights into the pathogenesis of HIV/SIV enteropathy and, possibly, other GI inflammatory conditions. Molecular mechanisms uncovered through these studies may open new miRNA-based strategies for the diagnosis and treatment of idiopathic GI disorders like AIDS enteropathy.

Public Health Relevance

The proposed study for the first time will investigate the role of small regulatory ribonucleic acids (microRNAs) in the pathogenesis of HIV/SIV enteropathy. HIV/SIV enteropathy is an idiopathic disorder that affects two-thirds of HIV infected patients and the exact causes still remain obscure. Studies of this kind will further enhance our understanding of the molecular pathogenesis of this order and will help develop better diagnostic and therapeutic strategies in the future.

Agency
National Institute of Health (NIH)
Type
Research Project (R01)
Project #
5R01DK083929-05
Application #
8688225
Study Section
AIDS Immunology and Pathogenesis Study Section (AIP)
Program Officer
Perrin, Peter J
Project Start
Project End
Budget Start
Budget End
Support Year
5
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Tulane University
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
City
New Orleans
State
LA
Country
United States
Zip Code
70118
Didier, E S; MacLean, A G; Mohan, M et al. (2016) Contributions of Nonhuman Primates to Research on Aging. Vet Pathol 53:277-90
Kumar, Vinay; Torben, Workineh; Kenway, Carys S et al. (2016) Longitudinal Examination of the Intestinal Lamina Propria Cellular Compartment of Simian Immunodeficiency Virus-Infected Rhesus Macaques Provides Broader and Deeper Insights into the Link between Aberrant MicroRNA Expression and Persistent Immune Activati J Virol 90:5003-19
Mohan, Mahesh; Chow, Cheryl-Emiliane T; Ryan, Caitlin N et al. (2016) Dietary Gluten-Induced Gut Dysbiosis Is Accompanied by Selective Upregulation of microRNAs with Intestinal Tight Junction and Bacteria-Binding Motifs in Rhesus Macaque Model of Celiac Disease. Nutrients 8:
Chandra, Lawrance C; Kumar, Vinay; Torben, Workineh et al. (2015) Chronic administration of Δ9-tetrahydrocannabinol induces intestinal anti-inflammatory microRNA expression during acute simian immunodeficiency virus infection of rhesus macaques. J Virol 89:1168-81
Pallikkuth, Suresh; Mohan, Mahesh (2015) Adipose Tissue: Sanctuary for HIV/SIV Persistence and Replication. Trends Microbiol 23:748-50
Mohan, Mahesh; Kumar, Vinay; Lackner, Andrew A et al. (2015) Dysregulated miR-34a-SIRT1-acetyl p65 axis is a potential mediator of immune activation in the colon during chronic simian immunodeficiency virus infection of rhesus macaques. J Immunol 194:291-306
Bhaskaran, M; Mohan, M (2014) MicroRNAs: history, biogenesis, and their evolving role in animal development and disease. Vet Pathol 51:759-74
Mohan, Mahesh; Chandra, Lawrance C; Torben, Workineh et al. (2014) miR-190b is markedly upregulated in the intestine in response to simian immunodeficiency virus replication and partly regulates myotubularin-related protein-6 expression. J Immunol 193:1301-13
Mohan, Mahesh; Kaushal, Deepak; Aye, Pyone P et al. (2013) Focused examination of the intestinal epithelium reveals transcriptional signatures consistent with disturbances in enterocyte maturation and differentiation during the course of SIV infection. PLoS One 8:e60122
Mohan, Mahesh; Kaushal, Deepak; Aye, Pyone P et al. (2012) Focused examination of the intestinal lamina propria yields greater molecular insight into mechanisms underlying SIV induced immune dysfunction. PLoS One 7:e34561