Potent inhibition of HIV-1 replication by mutants of epigenetic regulators, INI1 and associated SAP18-HDAC1 complex
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The interaction between HIV-1 and its host is complex and is mediated by host proteins that either restrict or promote HIV-1 replication. One such host protein is Integrase Interactor 1 (INI1) a core component of the SWI/SNF chromatin-remodeling complex that directly binds to HIV-1 integrase (IN) and is incorporated into virions via this interaction. In addition, INI1 interacts with Sin3a Associated Protein, 18kDa (SAP18), causing incorporation of multiple components of the Sin3a complex, including HDAC1, into HIV-1.;In an effort to characterize the functional importance of the INI1-mediated HDAC incorporation into virions, we analyzed the relationship between INI1 and its binding partners during late events in viral replication. We utilized mutants of INI1 which act in a transdominant negative manner to inhibit late events, and also characterized substitution mutants of INI1 which no longer interact with SAP18. Moreover, we employed the use of a catalytically inactive mutant of HDAC1 and assessed its role in viral replication. We show that minor changes to the INI1 protein have drastic effects on replication. The dominant-negative truncation mutant of INI1 precludes the proper trafficking and assembly of viral particles and is required in the cytoplasm for this activity. Moreover, aberrant processing of Gag takes place, resulting in the abnormal cytoplasmic distribution of Gag that is visualized. Similarly, point mutations in INI1 rendering it incapable of binding to SAP18, also potently inhibit late events and this inhibition is mediated through interaction with IN in the context of Gag/Pol. Mutants of INI1 defective for binding to SAP18 inhibit both total viral RNA levels and promote the degradation of Gag proteins. Finally, we found that HIV-1 virions selectively contain HDAC activity which is eliminated when virus is generated in the presence of catalytically inactive HDAC, and virion-associated HDAC was found to be required for a step post-entry and at or prior to reverse transcription.;Taken together, these studies indicate that over-expression of mutants of epigenetic regulators have profound inhibitory effects on several stages of HIV-1 replication. We propose that mimicking the effects of INI1 mutants may be a novel therapeutic strategy to severely reduce HIV replication.
Source: Dissertation Abstracts International, Volume: 72-01, Section: B, page: 1220.;Advisors: Ganjam V. Kalpana.