Role of INI1 /hSNF5 in HIV-1 replication: Association and requirement of a novel HDAC1 complex

dc.contributor.authorSorin, Masha
dc.date.accessioned2018-07-12T17:33:11Z
dc.date.available2018-07-12T17:33:11Z
dc.date.issued2004
dc.description.abstractVirus-host interactions involve an intricate interplay between the viral proteins and the cellular factors. Understanding the mechanisms underlying the pro-viral activities of the host factors, as well as the antiviral responses of the cell to HIV-1 infection present numerous novel strategies in developing therapeutics to combat AIDS.;Integration of the viral genome into the host chromosome is a key event in the lifecycle of all retroviruses, including human immunodeficiency virus type 1 (HIV-1). Virally encoded Integrase (IN) enzyme, which catalyzes the integration, has been shown to directly interact with the cellular protein Integrase Interactor 1 (INI1). Previous studies in our laboratory have demonstrated that a truncation mutant of INI1, containing minimal IN-interacting domain, potently inhibited HIV-1 virus particle assembly and release in the dominant-negative manner. INI1 was also found to be incorporated into HIV-1 particles [143]. In the current study I investigated the role of INI1 in HIV-1 replication by utilizing INI1-deficient cells derived from rhabdoid tumors, and using the RNA interference approach. I found that INI1 affects various steps of HIV-1 replication in the manner reminiscent of pleiotropic effects of IN. I further demonstrated that INI1 is specifically incorporated into HIV-1 particles, but not into other closely related lentiviruses, and showed that this incorporation is mediated by interaction of INI1 with HIV-1 IN.;I discovered that INI1-mediated effects on the early and late events of HIV-1 replication appear to be independent of INI association with the SWI/SNF chromatin remodeling complex. I showed that in the cells, INI1 associates the SIN3A/HDAC complex through direct binding with SAP18 protein, and this association is enhanced by HIV-1. This INI1-containing complex is specifically incorporated into HIV-1 particles in an IN-dependent manner, suggesting that direct interaction between INI1 and IN recruits this multiprotein complex into the virions. I further demonstrated that this INI1-SIN3/HDAC complex is important for infectivity of HIV-1 virions. I determined that the activity of the virus-associated HDAC1 is required for the early post-entry events of viral replication at or before the step of reverse transcription.;Our current working hypothesis is that interaction of INI1 with HIV-1 IN mediates recruitment of SIN3/HDAC complex into the HIV-1 virions, and this multiprotein complex is necessary for a step at or before reverse transcription.;The above results present an array of possibilities of potentially inhibiting HIV-1 replication by means of small molecular weight inhibitors targeting interactions of INI1 with IN and with SAP18, and by using existing and new HDAC inhibitors.
dc.identifier.citationSource: Dissertation Abstracts International, Volume: 65-07, Section: B, page: 3316.;Advisors: Ganjam V. Kalpana.
dc.identifier.urihttps://ezproxy.yu.edu/login?url=http://gateway.proquest.com/openurl?url_ver=Z39.88-2004&rft_val_fmt=info:ofi/fmt:kev:mtx:dissertation&res_dat=xri:pqm&rft_dat=xri:pqdiss:3140587
dc.identifier.urihttps://hdl.handle.net/20.500.12202/720
dc.publisherProQuest Dissertations & Theses
dc.subjectMolecular biology.
dc.titleRole of INI1 /hSNF5 in HIV-1 replication: Association and requirement of a novel HDAC1 complex
dc.typeDissertation

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