Regulation of Interferon Signaling by INI1/hSNF5 During HIV-1 Replication

Project: Research project

Project Details


[unreadable] DESCRIPTION (provided by applicant): The long-term goal of this proposal is to delineate the dynamic host-virus interactions during HIV-1 replication and use this information to develop novel and effective strategies to combat AIDS. INI1/hSNF5, is a HIV-1 integrase (IN) binding host factor, is a component of the mammalian chromatin-remodeling SWI/SNF complex involved in transcriptional regulation. INI1/hSNF5 directly and strongly binds to HIV-1 IN and a fragment of INI1/hSNF5, spanning the minimal IN-binding domain, dominant negatively inhibits HIV-1 replication. These observations suggested that INI1/hSNF5 interaction is required for HIV-1 replication. Recent studies demonstrate that INI1/hSNF5 is a tumor suppressor, biallelically mutated in rhabdoid tumors. Our attempt to study global gene expression profile revealed that INI1/hSNF5 stimulates a high degree of IFN signal induced genes (ISGs) and PML nuclear body proteins in INI1-/- rhabdoid cells. These results shed new insight on the role of INI1/hSNF5 in HIV-1 replication. We hypothesize that INI1 is a component of the cellular anti-viral defense (innate immunity) and is required for induction of IFN signaling during HIV-1 replication and that HIV-1 subverts the effect of INI1/hSNF5 by directly binding to it via IN and capturing it during its replication. To test this hypothesis, in the specific aim I we will determine if INI1/hSNF5 is required for inducing IFN signaling in T cells by IFNs, poly(I):(C) and during HIV-1 replication. We will monitor the induction of antiviral genes (e.g. IFIT1, IFITM1, OAS2, MX2 and PKR), PML nuclear body components (e.g. PML, Sp100, Sp110), and signal transducers (e.g. STAT1). We will correlate the effect of down-modulation of INI1 and ISG expression to HIV-1 replication. These results will establish if INI1/hSNF5 is a component of the cellular antiviral defense during HIV-1 replication. In the specific aim II we will determine if HIV-1 subverts the INI1-induced antiviral defense by capturing it via binding by IN. We will: (i) use a mutant HIV-1 virion harboring INI1-interaction-defective IN mutants (H12Y) and a transdominant mutant of INI1 (S6); determine if IN-mutants H12Y will be unable to capture INI1 and allow the IFN signaling; (ii) determine if S6 sequesters IN and allows cellular INI1 to mount IFN signaling and compare the effect S6 to an IN-interaction defective mutant of S6 (E3); (iii) To determine if IN within the context of Gag-Pol is able to sequester INI1, we will investigate the temporal relationship between expression of Gag-Pol, ISG expression and redistribution of endogenous INI1 during late events of HIV-1 replication. If Gag-Pol expression is able to sequester cellular INI1 in the cytoplasm, then this will lead to subversion of the ISG expression during HIV-1 replication. These results will shed light on the mechanism by which HIV-1 may subvert INI1-induced cellular antiviral defense. We hope that together the above two specific aims will establish a new paradigm in dynamic host-HIV-1 interaction and may provide insight for developing novel antiviral and vaccine strategies against AIDS. AIDS is still a major health problem because of the inability of current drugs to eliminate HIV-1 due to the emergence of the resistant viruses. Therefore, there is a dire need for identification of new targets and development of novel therapeutic strategies to combat AIDS. There is a dynamic interaction between host and the virus during pathogenesis. The aim of this application is to test a novel hypotheses that INI1/hSNF5, a cellular protein that binds to one of the HIV-1 proteins (integrase), is a component of the cellular antiviral defense and utilize this insight for developing novel antiviral strategies against AIDS in the future. [unreadable] [unreadable] [unreadable] [unreadable] [unreadable]
Effective start/end date9/30/078/31/09


  • National Institute of Allergy and Infectious Diseases: $244,269.00
  • National Institute of Allergy and Infectious Diseases: $207,500.00


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