LEDGF/p75-Independent HIV-1 Replication Demonstrates a Role for HRP-2 and Remains Sensitive to Inhibition by LEDGINs

PLoS Pathogens

Keshet Ronen¹  Frederic D. Bushman¹  Rik Gijsbers²  Zeger Debyser²  Jan De Rijck²  Jonas Demeulemeester²  Frauke Christ²  Rik Schrijvers²  Sofie Vets²  Noritaka Adachi³ 

[1] Department of Microbiology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, United States of America;Division of Molecular Medicine, Katholieke Universiteit Leuven, Leuven, Flanders, Belgium;Graduate School of Nanobioscience, Yokohama City University, Yokohama, Japan

关键词: HIV-1;    Viral replication;    Polymerase chain reaction;    HIV;    Cofactors (biochemistry);    Chromatin;    Gene expression;    Viral gene expression;   

DOI  :  10.1371/journal.ppat.1002558

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

Lens epithelium–derived growth factor (LEDGF/p75) is a cellular cofactor of HIV-1 integrase (IN) that interacts with IN through its IN binding domain (IBD) and tethers the viral pre-integration complex to the host cell chromatin. Here we report the generation of a human somatic LEDGF/p75 knockout cell line that allows the study of spreading HIV-1 infection in the absence of LEDGF/p75. By homologous recombination the exons encoding the LEDGF/p75 IBD (exons 11 to 14) were knocked out. In the absence of LEDGF/p75 replication of laboratory HIV-1 strains was severely delayed while clinical HIV-1 isolates were replication-defective. The residual replication was predominantly mediated by the Hepatoma-derived growth factor related protein 2 (HRP-2), the only cellular protein besides LEDGF/p75 that contains an IBD. Importantly, the recently described IN-LEDGF/p75 inhibitors (LEDGINs) remained active even in the absence of LEDGF/p75 by blocking the interaction with the IBD of HRP-2. These results further support the potential of LEDGINs as allosteric integrase inhibitors.

【 授权许可】

CC BY