The Lentiviral Integrase Binding Protein LEDGF/p75 and HIV-1 Replication

PLoS Pathogens

Alan Engelman¹  Peter Cherepanov² 

[1] Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute, Division of AIDS, Harvard Medical School, Boston, Massachusetts, United States of America;Division of Medicine, Imperial College London, St. Mary's Campus, London, United Kingdom

关键词: HIV-1;    Chromatin;    DNA-binding proteins;    DNA methylation;    Protein interactions;    Sequence motif analysis;    Cofactors (biochemistry);    DNA replication;   

DOI  :  10.1371/journal.ppat.1000046

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

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.

【 授权许可】

CC BY