LEDGF/p75-independent HIV-1 replication demonstrates a role for HRP-2 and remains sensitive to inhibition by LEDGINs.

Abstract

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.

• Authors: Rik Schrijvers, Jan De Rijck, Jonas Demeulemeester, Noritaka Adachi, Sofie Vets, Keshet Ronen, Frauke Christ, Frederic D Bushman, Zeger Debyser, Rik Gijsbers
• Journal: PLoS pathogens (PLoS Pathog) Vol. 8 Issue 3 Pg. e1002558 ( 2012) ISSN: 1553-7374 [Electronic] United States
• PMID: 22396646 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Adaptor Proteins, Signal Transducing
• HIV Integrase Inhibitors
• Intercellular Signaling Peptides and Proteins
• PSIP1 protein, human
• Pentanoic Acids
• Thiophenes
• Transcription Factors
• hepatoma-derived growth factor
• ledgin 7
• HIV Integrase
• p31 integrase protein, Human immunodeficiency virus 1

Topics

• Adaptor Proteins, Signal Transducing (genetics, metabolism)
• Catalytic Domain
• Gene Knockdown Techniques
• Gene Silencing
• HIV Integrase (metabolism)
• HIV Integrase Inhibitors (pharmacology)
• HIV-1 (drug effects, physiology)
• Host-Pathogen Interactions
• Humans
• Intercellular Signaling Peptides and Proteins (metabolism)
• Pentanoic Acids (pharmacology)
• Thiophenes (pharmacology)
• Transcription Factors (genetics, metabolism)
• Virus Replication (drug effects, genetics)