Host genetic factors and miRNA-linked dendritic cell responses associated with the outcome of treatment response in HIV-1/HCV co-infected individuals

Abstract HIV-1/HCV co-infection is a significant burden on global economy and public health. PEGylated interferon and ribavarin remain the essential components of anti-HCV treatment. We investigated the host genetic and immunological correlates of successful treatment response in conjunction with mechanisms by which PEG-IFN is able to clear the virus in a cohort of HIV-1/HCV co-infected individuals undergoing IFN/RBV treatment. First we demonstrate that functional state of DCs before/during therapy influences the treatment outcome. Upon genotyping IFNL3 polymorphisms rs12979860, rs4803217 and ss469415590, we found rs12979860 to be a better predictor of treatment outcome. Next, we compared the expression of forty-six IFN-stimulated genes prior to and after the treatment and observed that pre-treatment levels of several ISGs were higher in SVRs compared to NRs. In continuation, we identified miRNAs whose expression can be regulated by IFN in periphery. miRNA expression patterns in mDCs and pDCs in response to IFN-α were examined and observed miR-221 downregulation via IFN induced STAT3 inhibition in both. Using in-silico approaches followed by experimental validation, CDKN1C, CD54 and SOCS1 were identified as miR-221 targets. Moreover, miR-221 overexpression in mDCs enhanced their secretion of proinflammatory cytokines IL-6 and TNF-α but reduced the secretion of anti-inflammatory cytokine IL-10. These observations were extended and correlated with those obtained with patients’ PBMCs, hepatocytes and kupffer cells from HCV infected individuals as well as individuals with alcoholic cirrhosis. In summary, these studies demonstrated the role of IFN-α/miR-221 axis in HCV pathogenesis and response to IFN-based treatments.