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

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.