Allosteric Integrase Inhibitor Influences on HIV-1 Integration and Roles of LEDGF/p75 and HDGFL2 Host Factors
Allosteric integrase (IN) inhibitors (ALLINIs), which are promising preclinical compounds that engage the lens epithelium-derived growth factor (LEDGF)/p75 binding site on IN, can inhibit different aspects of human immunodeficiency virus 1 (HIV-1) replication. During the late phase of replication, A...
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| Format: | Article |
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MDPI AG
2022-08-01
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| Series: | Viruses |
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| Online Access: | https://www.mdpi.com/1999-4915/14/9/1883 |
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| author | Parmit Kumar Singh Wen Li Gregory J. Bedwell Hind J. Fadel Eric M. Poeschla Alan N. Engelman |
| author_facet | Parmit Kumar Singh Wen Li Gregory J. Bedwell Hind J. Fadel Eric M. Poeschla Alan N. Engelman |
| author_sort | Parmit Kumar Singh |
| collection | DOAJ |
| description | Allosteric integrase (IN) inhibitors (ALLINIs), which are promising preclinical compounds that engage the lens epithelium-derived growth factor (LEDGF)/p75 binding site on IN, can inhibit different aspects of human immunodeficiency virus 1 (HIV-1) replication. During the late phase of replication, ALLINIs induce aberrant IN hyper-multimerization, the consequences of which disrupt IN binding to genomic RNA and virus particle morphogenesis. During the early phase of infection, ALLINIs can suppress HIV-1 integration into host genes, which is also observed in LEDGF/p75-depelted cells. Despite this similarity, the roles of LEDGF/p75 and its paralog hepatoma-derived growth factor like 2 (HDGFL2) in ALLINI-mediated integration retargeting are untested. Herein, we mapped integration sites in cells knocked out for LEDGF/p75, HDGFL2, or both factors, which revealed that these two proteins in large part account for ALLINI-mediated integration retargeting during the early phase of infection. We also determined that ALLINI-treated viruses are defective during the subsequent round of infection for integration into genes associated with speckle-associated domains, which are naturally highly targeted for HIV-1 integration. Class II IN mutant viruses with alterations distal from the LEDGF/p75 binding site moreover shared this integration retargeting phenotype. Altogether, our findings help to inform the molecular bases and consequences of ALLINI action. |
| first_indexed | 2024-03-09T22:14:20Z |
| format | Article |
| id | doaj.art-7577eca5ddbd4533ae9c76d4eb51dcf4 |
| institution | Directory Open Access Journal |
| issn | 1999-4915 |
| language | English |
| last_indexed | 2024-03-09T22:14:20Z |
| publishDate | 2022-08-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Viruses |
| spelling | doaj.art-7577eca5ddbd4533ae9c76d4eb51dcf42023-11-23T19:25:43ZengMDPI AGViruses1999-49152022-08-01149188310.3390/v14091883Allosteric Integrase Inhibitor Influences on HIV-1 Integration and Roles of LEDGF/p75 and HDGFL2 Host FactorsParmit Kumar Singh0Wen Li1Gregory J. Bedwell2Hind J. Fadel3Eric M. Poeschla4Alan N. Engelman5Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA 02215, USADepartment of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA 02215, USADepartment of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA 02215, USADivision of Infectious Diseases, Mayo Clinic, Rochester, MN 55905, USADivision of Infectious Diseases, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USADepartment of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA 02215, USAAllosteric integrase (IN) inhibitors (ALLINIs), which are promising preclinical compounds that engage the lens epithelium-derived growth factor (LEDGF)/p75 binding site on IN, can inhibit different aspects of human immunodeficiency virus 1 (HIV-1) replication. During the late phase of replication, ALLINIs induce aberrant IN hyper-multimerization, the consequences of which disrupt IN binding to genomic RNA and virus particle morphogenesis. During the early phase of infection, ALLINIs can suppress HIV-1 integration into host genes, which is also observed in LEDGF/p75-depelted cells. Despite this similarity, the roles of LEDGF/p75 and its paralog hepatoma-derived growth factor like 2 (HDGFL2) in ALLINI-mediated integration retargeting are untested. Herein, we mapped integration sites in cells knocked out for LEDGF/p75, HDGFL2, or both factors, which revealed that these two proteins in large part account for ALLINI-mediated integration retargeting during the early phase of infection. We also determined that ALLINI-treated viruses are defective during the subsequent round of infection for integration into genes associated with speckle-associated domains, which are naturally highly targeted for HIV-1 integration. Class II IN mutant viruses with alterations distal from the LEDGF/p75 binding site moreover shared this integration retargeting phenotype. Altogether, our findings help to inform the molecular bases and consequences of ALLINI action.https://www.mdpi.com/1999-4915/14/9/1883HIV/AIDSantiretroviral inhibitorintegraseallosteric integrase inhibitorLEDGF/p75HDGFL2 |
| spellingShingle | Parmit Kumar Singh Wen Li Gregory J. Bedwell Hind J. Fadel Eric M. Poeschla Alan N. Engelman Allosteric Integrase Inhibitor Influences on HIV-1 Integration and Roles of LEDGF/p75 and HDGFL2 Host Factors Viruses HIV/AIDS antiretroviral inhibitor integrase allosteric integrase inhibitor LEDGF/p75 HDGFL2 |
| title | Allosteric Integrase Inhibitor Influences on HIV-1 Integration and Roles of LEDGF/p75 and HDGFL2 Host Factors |
| title_full | Allosteric Integrase Inhibitor Influences on HIV-1 Integration and Roles of LEDGF/p75 and HDGFL2 Host Factors |
| title_fullStr | Allosteric Integrase Inhibitor Influences on HIV-1 Integration and Roles of LEDGF/p75 and HDGFL2 Host Factors |
| title_full_unstemmed | Allosteric Integrase Inhibitor Influences on HIV-1 Integration and Roles of LEDGF/p75 and HDGFL2 Host Factors |
| title_short | Allosteric Integrase Inhibitor Influences on HIV-1 Integration and Roles of LEDGF/p75 and HDGFL2 Host Factors |
| title_sort | allosteric integrase inhibitor influences on hiv 1 integration and roles of ledgf p75 and hdgfl2 host factors |
| topic | HIV/AIDS antiretroviral inhibitor integrase allosteric integrase inhibitor LEDGF/p75 HDGFL2 |
| url | https://www.mdpi.com/1999-4915/14/9/1883 |
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