title: miR-190b is markedly upregulated in the intestine in response to simian immunodeficiency virus replication and partly regulates myotubularin-related protein-6 expression.
abstract: HIV replication and the cellular micro-RNA (miRNA) machinery interconnect at several posttranscriptional levels. To understand their regulatory role in the intestine, a major site of HIV/SIV replication, dissemination, and CD4(+) T cell depletion, we profiled miRNA expression in colon following SIV infection (10 acute SIV, 5 uninfected). Nine (four up and five down) miRNAs showed statistically significant differential expression. Most notably, miR-190b expression showed high statistical significance (adjusted p = 0.0032), the greatest fold change, and was markedly elevated in colon and jejunum throughout SIV infection. In addition, miR-190b upregulation was detected before peak viral replication and the nadir of CD4(+) T cell depletion predominantly in lamina propria leukocytes. Interestingly non-SIV-infected macaques with diarrhea and colitis failed to upregulate miR-190b, suggesting that its upregulation was neither inflammation nor immune-activation driven. SIV infection of in vitro-cultured CD4(+) T cells and primary intestinal macrophages conclusively identified miR-190b upregulation to be driven in response to viral replication. Further miR-190b expression levels in colon and jejunum positively correlated with tissue viral loads. In contrast, mRNA expression of myotubularin-related protein 6 (MTMR6), a negative regulator of CD4(+) T cell activation/proliferation, significantly decreased in SIV-infected macrophages. Luciferase reporter assays confirmed MTMR6 as a direct miR-190b target. To our knowledge, this is the first report, which describes dysregulated miRNA expression in the intestine, that identifies a potentially significant role for miR-190b in HIV/SIV pathogenesis. More importantly, miR-190b-mediated MTMR6 downregulation suggests an important mechanism that could keep infected cells in an activated state, thereby promoting viral replication. In the future, the mechanisms driving miR-190b upregulation including other cellular processes it regulates in SIV-infected cells need determination.
authors: Division of Comparative Pathology, Tulane National Primate Research Center, Covington, LA 70433 mmohan@tulane.edu.
authors: Mahesh
authors: M
authors: Mohan
authors: Division of Comparative Pathology, Tulane National Primate Research Center, Covington, LA 70433.
authors: Lawrance C
authors: LC
authors: Chandra
authors: Division of Comparative Pathology, Tulane National Primate Research Center, Covington, LA 70433.
authors: Workineh
authors: W
authors: Torben
authors: Division of Comparative Pathology, Tulane National Primate Research Center, Covington, LA 70433.
authors: Pyone P
authors: PP
authors: Aye
authors: Division of Comparative Pathology, Tulane National Primate Research Center, Covington, LA 70433.
authors: Xavier
authors: X
authors: Alvarez
authors: Division of Comparative Pathology, Tulane National Primate Research Center, Covington, LA 70433.
authors: Andrew A
authors: AA
authors: Lackner
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000821:virology; D003106:Colon / Q000276:immunology / Q000378:metabolism / Q000821:virology; D015536:Down-Regulation / Q000235:genetics / Q000276:immunology; D017930:Genes, Reporter; D007413:Intestinal Mucosa / Q000276:immunology / Q000378:metabolism* / Q000821:virology; D007583:Jejunum / Q000276:immunology / Q000378:metabolism / Q000821:virology; D008156:Luciferases / Q000235:genetics; D008253:Macaca mulatta; D035683:MicroRNAs / Q000096:biosynthesis / Q000235:genetics*; D054558:Protein Tyrosine Phosphatases, Non-Receptor / Q000096:biosynthesis / Q000235:genetics*; D012367:RNA, Viral / Q000235:genetics / Q000276:immunology; D015301:Retroviruses, Simian / Q000235:genetics* / Q000276:immunology; D016097:Simian Acquired Immunodeficiency Syndrome / Q000235:genetics* / Q000276:immunology; D015302:Simian Immunodeficiency Virus / Q000235:genetics* / Q000276:immunology; D015854:Up-Regulation / Q000235:genetics* / Q000276:immunology; D014779:Virus Replication / Q000235:genetics* / Q000276:immunology
chemical_list: D035683:MicroRNAs; D012367:RNA, Viral; D008156:Luciferases; D054558:Protein Tyrosine Phosphatases, Non-Receptor