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Updated: Aug 27, 2025
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Amplification, Next-generation Sequencing, and Genomic DNA Mapping of Retroviral Integration Sites
Published on: March 22, 2016
17.8K
Allosteric Integrase Inhibitor Influences on HIV-1 Integration and Roles of LEDGF/p75 and HDGFL2 Host Factors
Parmit Kumar Singh1,2, Wen Li1,2, Gregory J Bedwell1,2
1Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
Viruses
|September 23, 2022
Summary
Allosteric integrase inhibitors (ALLINIs) redirect HIV-1 integration by targeting LEDGF/p75 and HDGFL2. These compounds impact viral replication and integration site selection.
Area of Science:
- Virology
- Molecular Biology
- Drug Discovery
Background:
- Allosteric integrase inhibitors (ALLINIs) are preclinical compounds targeting the HIV-1 integrase (IN) lens epithelium-derived growth factor (LEDGF)/p75 binding site.
- ALLINIs inhibit HIV-1 replication through various mechanisms, including disrupting IN binding to genomic RNA and affecting virus particle morphogenesis during late-stage replication.
- During early infection, ALLINIs suppress HIV-1 integration into host genes, similar to LEDGF/p75-depleted cells.
Purpose of the Study:
- To investigate the roles of LEDGF/p75 and its paralog HDGFL2 in ALLINI-mediated HIV-1 integration site retargeting.
- To determine the impact of ALLINIs on HIV-1 integration into specific host gene categories, such as speckle-associated domains.
- To compare the integration retargeting phenotype of ALLINI-treated viruses with that of Class II IN mutant viruses.
Main Methods:
- Mapping HIV-1 integration sites in cells with genetic knockouts for LEDGF/p75, HDGFL2, or both.
- Analyzing the integration site profiles of viruses treated with ALLINIs.
- Characterizing integration patterns of Class II IN mutant viruses.
Main Results:
- LEDGF/p75 and HDGFL2 largely account for ALLINI-mediated integration retargeting during early HIV-1 infection.
- ALLINI-treated viruses exhibit defects in integrating into speckle-associated domain genes in subsequent infection rounds.
- Class II IN mutant viruses display similar integration retargeting phenotypes, suggesting distal alteration effects.
Conclusions:
- LEDGF/p75 and HDGFL2 are key mediators of HIV-1 integration site selection influenced by ALLINIs.
- ALLINIs induce specific integration retargeting, impacting the targeting of genes like speckle-associated domains.
- Findings elucidate the molecular mechanisms and consequences of ALLINI action on HIV-1 replication and integration.
Keywords:
HDGFL2HIV integrationHIV/AIDSLEDGF/p75allosteric integrase inhibitorantiretroviral inhibitorintegrasenuclear specklesspeckle-associated domainsMore Related Videos
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