Cystatin B and HIV regulate the STAT-1 signaling circuit in HIV-infected and INF-β-treated human macrophages
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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 (STAT-1) factor and inhibits the interferon (IFN-β) response in Vero cells by preventing STAT-1 translocation to the nucleus. Cystatin B also decreases the levels of tyrosine-phosphorylated STAT-1 (STAT-1PY). However, the mechanisms of cystatin B regulation on STAT-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 STAT-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 STAT-1 localization and activation using immunofluorescence and proximity ligation assays. Cystatin B decreased STAT-1PY and its transportation to the nucleus, while HIV infection retained unphosphorylated STAT (USTAT-1) 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, USTAT-1 and STAT-1PY. These results demonstrate that cystatin B interferes with the STAT-1 signaling and IFN-β-antiviral responses perpetuating HIV in macrophage reservoirs.
KeywordsHIV Cystatin B STAT-1 Macrophages IFN-β
We thank Dr. Howard Gendelman for providing HIV-ADA and Lic. Bismark Madera from the Confocal Image Facility at the University of Puerto Rico-Rio Piedras Campus. This work was supported in part by NIH grants F32 MH094210, R01 AI094603, R01 MH08316, U54 NS431, ISI0 RR-13705-01, and DBI-0923132 to establish and upgrade the Confocal Microscopy Facility at the University of Puerto Rico (CIF-UPR), and institutional funds from University of Puerto Rico Presidency. We thank the 8U54MD007587-03 (RCMI Clinical and Translational Research award, University of Puerto Rico Medical Sciences Campus) from the National Institute on Minority Health and Health Disparities (NIMHD) and the editorial services of Dr. Deana Hallman from the Puerto Rico Clinical and Translational Research Consortium, which are supported by the National Institute on Minority Health and Health Disparities of the National Institutes of Health under Award Number 2U54MD007587. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
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Conflict of Interest
LMM has a patent application approved for cystatin B, related to this manuscript. Pat No. 8,143,231.
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