title: Cystatin B and HIV regulate the STAT-1 signaling circuit in HIV-infected and INF-β-treated human macrophages.
abstract: 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.
authors.affiliation: Universidad del Este, Carolina, PR, 00984, USA.
authors.forename: L E
authors.initials: LE
authors.lastname: Rivera
authors.affiliation: Department of Microbiology and Medical Zoology, University of Puerto Rico-Medical Sciences Campus, San Juan, PR, 00935, USA.
authors.forename: E
authors.initials: E
authors.lastname: Kraiselburd
authors.affiliation: Department of Microbiology and Medical Zoology, University of Puerto Rico-Medical Sciences Campus, San Juan, PR, 00935, USA. loyda.melendez@upr.edu.
authors.forename: L M
authors.initials: LM
authors.lastname: Meléndez
mesh_terms: D002467:Cell Nucleus / Q000187:drug effects / Q000276:immunology / Q000821:virology; D055313:Cystatin B / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000276:immunology; D005786:Gene Expression Regulation; D015497:HIV-1 / Q000254:growth & development / Q000276:immunology*; D054884:Host-Pathogen Interactions; D006801:Humans; D016899:Interferon-beta / Q000494:pharmacology*; D008264:Macrophages / Q000187:drug effects* / Q000276:immunology / Q000821:virology; D010766:Phosphorylation / Q000187:drug effects; D061251:Primary Cell Culture; D021381:Protein Transport / Q000187:drug effects; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D050794:STAT1 Transcription Factor / Q000235:genetics* / Q000276:immunology; D015398:Signal Transduction; D014162:Transfection; D014779:Virus Replication / Q000187:drug effects
chemical_list: C524994:CSTB protein, human; D034741:RNA, Small Interfering; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D016899:Interferon-beta; D055313:Cystatin B
keywords: Cystatin B; HIV; IFN-β; Macrophages; STAT-1