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

Date

2004

Authors

Sorin, Masha

Journal Title

Journal ISSN

Volume Title

Publisher

ProQuest Dissertations & Theses

YU Faculty Profile

Abstract

Virus-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.

Description

Keywords

Molecular biology.

Citation

Source: Dissertation Abstracts International, Volume: 65-07, Section: B, page: 3316.;Advisors: Ganjam V. Kalpana.