AIDS continues to be a major global health problem. One reason for failure to develop an effective vaccine against AIDS is the ability of HIV-1 to subvert and/or evade host innate as well as cellular immune responses. A long-term goal of our proposal is to understand complex host-virus interaction and develop strategies to inhibit HIV-1 replication by this understanding. INI1/hSNF5 is a component of the chromatin remodeling SWI/SNF complex that directly and selectively binds to HIV-1 integrase (IN). Both HIV-1 integrase and INI1/hSNF5 bind to SAP18 (Sin3a-associated protein 18), a component of the Sin3a-HDAC1 (histone deacetylase 1) complex, and mediate the recruitment of the components of HDAC1 complex into HIV-1 virions. The significance of IN-INI1-SAP18-HDAC1 interactions is not understood. Mutants of INI1 (S6 and SAP18- Interaction Defective mutants of INI1, SID-INI1*) potently inhibit (1000-10,000 fold) HIV-1 late events. INI1 siRNA in producer cells inhibits HIV-1 particle production. Many of the INI1-interaction-defective IN mutants are blocked at post entry early reverse transcription events. These studies indicate that INI1 is required for HIV-1 replication at multiple stages. However, some reports indicate that knockdown of endogenous INI1 by siRNA in target cells enhances HIV-1 replication, indicating that INI1 has an antiviral role. Thus INI1 has a dual effect on HIV-1 replication. Recent evidence indicates that INI1/hSNF5 and SWI/SNF complex are involved in inducing interferon signaling. We propose a novel hypothesis that the dual effects of INI1 on HIV-1 replication stems from the HIV-1 efforts to subjugate the cellular antiviral function. In producer cells, binding of INI1-SAP18-HDAC1 to IN is needed for efficient particle production and for early post entry events such as uncoating and/or reverse transcription. Furthermore, sequestration of INI1-SAP18 complex by HIV-1 may lead to subversion of interferon response. In target cells, endogenous INI1 is antiviral, where it induces interferon-stimulated genes (ISGs). We will investigate each of these roles of INI1 in this proposal. To determine the role of INI1 in early events, we will determine the nature and mechanism of defect caused by IID-IN* mutants (Aim I). To determine the role of INI1-SAP18 interactions in late events, we will characterize the defect caused by SID-INI1* mutants (Aim II). We will determine if defects in interferon response abrogates the antiviral effects of INI1 and INI1 mutants (Aim III). Our proposal is likely to shed new light on the role of IN and INI1 in late events and in post entry mechanisms including uncoating. Understanding of the mechanism of profound inhibitory effects of INI1 mutants (S6 and SID-INI1*) may facilitate the development of novel strategies to inhibit HIV-1 replication. These studies not only will fill our gaps in understanding of HIV-1 replication, but also have a wider impact on the understanding of innate immunity and how HIV-1 may have evolved to suppress this function and may open up new avenues for the development of effective vaccines and strategies to inhibit HIV-1 replication.
NIH ExPorter
NIH ExPorter