Here, we describe new information on changes in the lncRNA landscape and their potential role in the pathogenesis of HIV/SIV induced intestinal epithelial dysfunction. Our study provides relevant novel insights on the protective role of the natural anti-sense lncRNA MMP25-AS1 in the colonic epithelium (CE) and its modulation by long-term controlled delta-9-tetrahydrocannabinol (THC) administration during chronic HIV/SIV infection. More specifically, we demonstrate a novel epigenetic mechanism in maintaining intestinal homeostasis by MMP25-AS1 upregulated by THC in CE via direct counteraction of matrix metalloproteinase 25 (MMP25) expression. Overall design: Differentially expressed lncRNAs and mRNAs was profiled in the CE of chronically SIV infected RMs administered either THC (n = 6, duration = 6 months) or VEH (n = 5, duration = 6 months) and uninfected control (n = 6) animals