Abstract
Retroviral replication proceeds through a stable proviral DNA intermediate, and numerous host cell factors have been implicated in its formation. In particular, recent results have highlighted an important role for the integrase-interactor lens epithelium-derived growth factor (LEDGF)/p75 in lentiviral integration. Cells engineered to over-express fragments of LEDGF/p75 containing its integrase-binding domain but lacking determinants essential for chromatin association are refractory to HIV-1 infection. Furthermore, both the levels of HIV-1 integration and the genomic distribution of the resultant proviruses are significantly perturbed in cells devoid of endogenous LEDGF/p75 protein. A strong bias towards integration along transcription units is a characteristic feature of lentiviruses. In the absence of LEDGF/p75, HIV-1 in large part loses that preference, displaying concomitant integration surges in the vicinities of CpG islands and gene promoter regions, elements naturally targeted by other types of retroviruses. Together, these findings highlight that LEDGF/p75 is an important albeit not strictly essential cofactor of lentiviral DNA integration, and solidify a role for chromatin-associated LEDGF/p75 as a receptor for lentiviral preintegration complexes. By now one of the best characterized virus–host interactions, the integrase-LEDGF/p75 interface opens a range of opportunities for lentiviral vector targeting for gene therapy applications as well as for the development of novel classes of antiretroviral drugs.
Highlights
A key step in the retroviral lifecycle is the formation of the provirus, the integrated form of the viral cDNA that is produced during reverse transcription
This review focuses on the IN interactor lens epithelium-derived growth factor (LEDGF)/transcriptional coactivator p75, whose critical role in lentiviral DNA integration has been highlighted by a number of recent studies [14,15,16,17,18]
LEDGF/p75 is an important host factor commandeering the integration of HIV-1 and likely other lentiviruses to active transcription units (TUs) [14,18]
Summary
A key step in the retroviral lifecycle is the formation of the provirus, the integrated form of the viral cDNA that is produced during reverse transcription. Initial RNAi-based studies were central to establish important links between endogenous LEDGF/p75 protein and lentiviral IN expression levels and subcellular localization, yet they failed to reveal an important role for the cell factor in HIV-1 replication. Significantly reduced levels of HIV-1 infection were observed in mouse embryo fibroblasts (MEFs) derived from LEDGF knockout as compared to littermate control animals [18] The block in both cases was at integration: reverse transcription and the formation of two long terminal repeat (LTR)–containing DNA circles, a surrogate marker for PIC nuclear import, were normal, whereas integration was severely reduced [16,18]. The model accounts for the retention of the weakly favored target DNA consensus sequence at the sites of HIV-1 integration [82,83,84,85] in the absence of LEDGF/ p75 [18], and explains why a detectable shift in the distribution of HIV-1 integration sites occurred under partial LEDGF/p75 knockdown conditions that were insufficiently weak to affect the overall level of virus infection [14]
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