ROLE OF MICRORNAS IN THE MOLECULAR PATHOGENESIS OF HIV/SIV ENTEROPATHY

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. The Gastrointestinal tract (GIT) is a major target of HIV/SIV infection. Although our understanding of HIV/SIV enteropathy has greatly improved, the recent discovery of miRNAs has added yet another novel and complex regulator of gene expression with potential roles in the molecular pathogenesis of this disorder. microRNAs (miRNAs) are genomically transcribed, ~21-23 nucleotide noncoding RNAs that are highly conserved and suppress gene expression by targeting mRNAs for translational repression or degradation. We investigated the contribution of miRNAs to GIT disease and inflammation using the SIV-infected rhesus macaque model. Colon tissue was collected at necropsy from 8 acutely SIV-infected (G1) (n=3, 8 days post SIV infection and n=5, 13-30 days post SIV infection) and 5 uninfected control macaques (G2). The contribution of miRNAs to GIT disease and inflammation was investigated using TaqMan Low Density Array (TLDA), QRT-PCR, In situ hybridization/Immunofluorescence and histopathology. Approximately 70% of the 377 miRNAs on card A and 50% of the 377 miRNAs on card B cross-reacted with the rhesus macaque. Following data analysis using STATMINER we identified a total of 25 card A and 12 card B miRNAs to be differentially expressed (p 0.05) in response to SIV infection. Important differentially expressed card A miRNAs included miR-1, -26a, -29c, -34a, -125b, -126, -130a, -133b, -135a, -140-5p, -let7b, -let7c, -222, -224, -383. Similarly, notable differentially expressed card B miRNAs included -190b, -550, -1247. QRT-PCR to further confirm TLDA expression profiles and in situ hybridization studies to identify specific cell types expressing these miRNAs are currently in progress. Our findings suggest that deregulation in cell/tissue-specific expression of miRNAs occurring in response to HIV/SIV infection may disrupt the functional relationship between the intestinal epithelium and the mucosal immune system causing alterations in intestinal structure and function.