MON-100 Unique miRNA Signature in HIV Lipodystrophy with Reduced Adipose Dicer Expression

Suppression of Dicer, an endoribonuclease that regulates microRNAs(miRNA), has evolved as a viral mechanism to enhance host HIV infectivity and may have unintended metabolic consequences. Animal knockout models of adipose-specific dicer(ADicer) acquire lipodystrophy accompanied by severe metabolic abnormalities. Data show adipose is a source of exosomal miRNAs, functioning as adipokines influencing metabolic homeostasis. We hypothesized a unique miRNA profile among individuals well-phenotyped for HIV lipodystrophy and reduced ADicer expression. We evaluated >1000 miRNAs from exosomes derived from sera among the 27 male individuals [9 HIV lipodystrophy(HIV/lipo), 9 HIV without lipodystrophy(HIV/non-lipo), 9 non-HIV] whom we previously showed variations in ADicer: most suppressed among HIV lipo, followed by HIV non-lipo and non-HIV (2.49[0.02,4.88] vs. 11.20[4.83,21.45] vs. 17.69[10.72,47.91],P=.002). To estimate miRNA abundance, data was normalized using the geomean of expressed Ct values. A false discovery rate analysis(FDR) was applied. We investigated whether significant exosomal miRNAs demonstrated a similar pattern in corresponding subcutaneous adipose tissue(SAT) samples. Using target prediction databases (TargetScan, miRDB, Diana), we identified genes related to fat biology (target score ≥85%) with clinical relevance to lipodystrophic phenotypes and further evaluated these in the adipose depot. HIV/lipo individuals(age 56±3years, BMI 30±1kg/m(2), duration HIV 24±2years, duration ART 20±2years, CD4+ count 482±90cells/μl, undetectable VL 67%) were similar to HIV/non-lipo(age 52±3 years, BMI 30±1 kg/m(2)) and non-HIV(age 55±3years, BMI 30±1kg/m(2)) individuals. Reduced ADicer expression was significantly related to reduced CD4(+) count(r=0.55,P=.02), duration ART use(r=-0.70,P=.001) and tended to be related to duration HIV(r=-0.44,P=.07) and reduced CD8(+) count(r=0.42,P=.08). Applying FDR, we detected exosomal miRNA-20a-3p(P=.0026), 324-5p(P=.0059), and 186-5p(P=.0977) were expressed differentially in HIV/lipo vs. non-HIV and 324-5p(P=.0348) in HIV/lipo vs. HIV/non-lipo. We further confirmed that miRNA-20a-3p was significantly and differentially expressed in the SAT, expressed highest in HIV lipo followed by HIV non-lipo and non-HIV [9.73±12.38 vs. 2.24±1.84 vs. 1.02±0.19, P<0.05] in a pattern similar to the exosomal profiles. Relevant miRNA and their target genes which tended to be differentially expressed in the SAT of HIV lipo vs. HIV non-lipo include: 20a-3p (TDG, P=0.07) and 186-5p (PDE10A, PID1; P<0.05). Altered ADicer expression and specific exosomal miRNAs may affect gene expression of regulators important to fat biology and metabolic homeostasis in HIV. In particular, miRNA-20a-3p may function as an adipokine demonstrating similar expression profiles in exosomes and adipose tissue of individuals with HIV lipodystrophy.