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 miRNA machinery interconnect at several post-transcriptional 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 (4-up and 5-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. Additionally, 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 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. This first report describing dysregulated miRNA expression in the intestine 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 future, the mechanisms driving miR-190b upregulation including other cellular processes it regulates in SIV-infected cells needs determination.

Chronic Administration of Δ 9 -Tetrahydrocannabinol Induces Intestinal Anti-Inflammatory MicroRNA Expression during Acute Simian Immunodeficiency Virus Infection of Rhesus Macaques

“…For instance, several in vitro studies have shown altered miRNA expression in response to HIV infection (30)(31)(32)(33)(34), and recent miRNA profiling studies performed on brain (35) and plasma samples (36) provide strong evidence of their dysregulation during SIV infection. In addition, we recently reported miR-190b to be significantly upregulated in the intestine at all stages of SIV infection (37) and that viral replication rather than infection-related inflammatory responses induced miR-190b upregulation (37). Further, we also confirmed MTMR6, a PIP3 phosphatase and an inhibitor of CD4 ϩ T cell proliferation and activation, to be a direct miR-190b target (37).…”

“…In addition, we recently reported miR-190b to be significantly upregulated in the intestine at all stages of SIV infection (37) and that viral replication rather than infection-related inflammatory responses induced miR-190b upregulation (37). Further, we also confirmed MTMR6, a PIP3 phosphatase and an inhibitor of CD4 ϩ T cell proliferation and activation, to be a direct miR-190b target (37).…”

“…Similarly, SIV RNA levels in duodenal tissue were quantified in tissues preserved in RNAlater (Life Technologies) as described before (37) and normalized to milligrams of total RNA.…”

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 Activation

“…Lately, the enhanced expression of miR-21 (13) and miR-142 (14) was correlated with macrophage activation and encephalitis in the brain of SIV-infected rhesus macaques. Focusing on the GI tract, an important site of CD4 ϩ T-cell depletion and HIV/SIV replication, we (15,16) and others (17) reported significant miRNA dysregulation in intact colon during SIV infection. Unlike our two previous studies that utilized intact intestinal tissue (15,16), in the present study, we focused exclusively on the intestinal lamina propria compartment to obtain a deeper understanding of the link between aberrant miRNA expression and chronic immune activation/inflammation in the intestine.…”

“…Focusing on the GI tract, an important site of CD4 ϩ T-cell depletion and HIV/SIV replication, we (15,16) and others (17) reported significant miRNA dysregulation in intact colon during SIV infection. Unlike our two previous studies that utilized intact intestinal tissue (15,16), in the present study, we focused exclusively on the intestinal lamina propria compartment to obtain a deeper understanding of the link between aberrant miRNA expression and chronic immune activation/inflammation in the intestine. In tune with this objective, we collected serial intestinal resection segments from the same animals before and at 21, 90, and 180 dpi and separated the different mucosal compartments (epithelium, intraepithelial lymphocytes, lamina propria leukocytes [LPLs], and fibrovascular stroma).…”