Cystatin B and HIV regulate the STAT-1 signaling circuit in HIV-infected and INF-β-treated human macrophages.

Cystatin B is a cysteine protease inhibitor that induces HIV replication in monocyte-derived macrophages (MDM). This protein interacts with signal transducer and activator of transcription factor and inhibits the interferon (IFN-β) response in Vero cells by preventing translocation to the nucleus. Cystatin B also decreases the levels of tyrosine-phosphorylated duanyu1813-1 However, the mechanisms of cystatin B regulation on duanyu1813-1 phosphorylation in MDM are unknown. We hypothesized that cystatin B inhibits IFN-β antiviral responses and induces HIV replication in macrophage reservoirs through the inhibition of duanyu1813-1 phosphorylation. Macrophages were transfected with cystatin B siRNA prior to interferon-β treatment or infected with HIV-ADA to determine the effect of cystatin B modulation in duanyu1813-1 localization and activation using immunofluorescence and proximity ligation assays. Cystatin B decreased and its transportation to the nucleus, while HIV infection retained unphosphorylated in the nucleus avoiding its exit to the cytoplasm for eventual phosphorylation. In IFN-β-treated MDM, cystatin B inhibited the nuclear translocation of both, and These results demonstrate that cystatin B interferes with the duanyu1813-1 signaling and IFN-β-antiviral responses perpetuating HIV in macrophage reservoirs.

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