Abstract
The integration of a DNA copy of the viral RNA genome into host chromatin is the defining step of retroviral replication. This enzymatic process is catalyzed by the virus-encoded integrase protein, which is conserved among retroviruses and LTR-retrotransposons. Retroviral integration proceeds via two integrase activities: 3′-processing of the viral DNA ends, followed by the strand transfer of the processed ends into host cell chromosomal DNA. Herein we review the molecular mechanism of retroviral DNA integration, with an emphasis on reaction chemistries and architectures of the nucleoprotein complexes involved. We additionally discuss the latest advances on anti-integrase drug development for the treatment of AIDS and the utility of integrating retroviral vectors in gene therapy applications.
Highlights
Retroviral species gained prominence as research models, for historical reasons or as animal pathogens
IN was identified as the protein product encoded within the 3′ portion of the retroviral pol gene that was essential for efficient retroviral replication and integration.[8−11] Reverse transcription of the diploid retroviral RNA genome results in the formation of a linear double-stranded viral DNA molecule carrying a copy of the long terminal repeat (LTR) sequence at either end.[12−15] The vDNA molecule exists in the form of a preintegration complex (PIC)[16,17] that is rather poorly biophysically characterized due to the scarce level at which it forms, ca. one copy per cell, during acute virus infection
Disruption of the IN coding portion of the HIV-1 pol gene can lead to production of viral particles with aberrant morphology and severe defects in reverse transcription.[28−31] only a minority of HIV-1 IN mutants display defects solely at the integration step of the viral life cycle
Summary
Replication via formation of a stable DNA form makes retroviruses amenable to reverse genetics. PICs have been reported to contain a number of cellular and viral proteins, most notably IN.[18−26] Once the PIC gains access to the nuclear compartment, the vDNA ends are inserted into a cellular chromosome This step, initiated by the enzymatic action of IN and completed by the host cell DNA repair machinery, is a point of no return: the cell becomes a permanent carrier of the integrated viral genome, which is referred to as the provirus. HIV-1 IN was shown to interact with the viral RT and influence its activity in vitro.[42−44] More recent work with allosteric IN inhibitors (described at length below) has highlighted a direct role for IN in HIV-1 particle maturation.[45−47] Among the esoteric functions of HIV-1 IN, its proposed involvement in PIC nuclear import has been the subject of considerable and yet to be resolved debate.[34,40,41,48−54]
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