Chronic immune activation/inflammation driven by factors like microbial translocation is a key determinant of human immunodeficiency virus/simian immunodeficiency virus (HIV/SIV) disease progression. Although extensive research on inflammation has focused on studying protein regulators, increasing evidence suggests a critical role for microRNAs (miRNAs) in regulating several aspects of the immune/inflammatory response and immune cell proliferation, differentiation, and activation. To understand their immunoregulatory role, we profiled miRNA expression sequentially in intestinal lamina propria leukocytes (LPLs) of eight macaques before and at 21, 90, and 180 days postinfection (dpi). At 21 dpi, ∼20 and 9 miRNAs were up- and downregulated, respectively. However, at 90 dpi (n = 60) and 180 dpi (n = 44), ≥75% of miRNAs showed decreased expression. Notably, the T-cell activation-associated miR-15b, miR-142-3p, miR-142-5p, and miR-150 expression was significantly downregulated at 90 and 180 dpi. Out of ∼10 downregulated miRNAs predicted to regulate CD69, we confirmed miR-92a to directly target CD69. Interestingly, the SIV-induced miR-190b expression was elevated at all time points. Additionally, elevated lipopolysaccharide (LPS)-responsive miR-146b-5p expression at 180 dpi was confirmed in primary intestinal macrophages following LPS treatment in vitro Further, reporter and overexpression assays validated IRAK1 (interleukin-1 receptor 1 kinase) as a direct miR-150 target. Furthermore, IRAK1 protein levels were markedly elevated in intestinal LPLs and epithelium. Finally, blockade of CD8(+) T-cell activation/proliferation with delta-9 tetrahydrocannabinol (Δ(9)-THC) significantly prevented miR-150 downregulation and IRAK1 upregulation. Our findings suggest that miR-150 downregulation during T-cell activation disrupts the translational control of IRAK1, facilitating persistent gastrointestinal (GI) inflammation. Finally, the ability of Δ(9)-THC to block the miR-150-IRAK1 regulatory cascade highlights the potential of cannabinoids to inhibit persistent inflammation/immune activation in HIV/SIV infection.
Pubmed ID: 26937033 RIS Download
Publication data is provided by the National Library of Medicine ® and PubMed ®. Data is retrieved from PubMed ® on a weekly schedule. For terms and conditions see the National Library of Medicine Terms and Conditions.
Center focused on understanding human health problems, including infectious diseases that require the use of nonhuman primates to develop diagnostics, therapeutics and preventive strategies. Primary research interests include developing vaccines, treatments and diagnostic tools for infectious diseases such as AIDS, tuberculosis, CMV, COVID-19, Lyme disease, and malaria. TNPRC has both biosafety level 2 and biosafety level 3 laboratories facilities to accommodate various research needs, and is the only National Primate Research Center with Regional Biosafety Laboratory.
View all literature mentions