Contact details
Dr Peter P Cherepanov
Division of Medicine
4th Floor, Medical School
Norfolk Place
St Mary's Campus
Tel: +44 (0)20 7594 3655
Dr Peter Cherepanov
Retroviral DNA integration
To establish productive infection HIV must insert a DNA replica of its genome into a host cell chromosome. The obligatory integration is a hallmark of retroviral replication and defines a point of no return in the infection, the cell becoming a permanent carrier of the proviral DNA. The catalytic events associated with integration, DNA cleavage and strand transfer, are carried out by the virus-derived enzyme integrase. Retroviral integrases are structurally and mechanistically related to a diverse group of enzymes including bacterial and eukaryotic transposases, V(D)J recombinase RAG1/2, Ribonuclease H, and the catalytic subunit of the RNA-induced silencing complex (RISC).
This superfamily is distinguished by the characteristic structural fold, organization of the active site and metal-dependent catalysis. One of the three essential retroviral enzymes, integrase is an important drug target. Selective inhibitors of HIV integrase are very effective antivirals.
Possessing only very limited coding capacity, retroviruses are masters in reprogramming and taking over host cell environment. Although many aspects of integration remain enigmatic, it is clear that it heavily relies on cellular machinery that protects viral cDNA, transports it into the nucleus, directs it to a transcriptionally-active chromatin region, and finally repairs integration intermediates. Several cellular proteins have been suggested to participate in HIV integration, some of them physically interacting with integrase protein. A human chromatin-associated protein LEDGF is the dominant interactor of HIV integrase in human cells. This transcription factor binds HIV integrase, modulates its enzymatic activity, tethers the viral protein to chromatin and contributes to the propensity of lentiviruses to integrate within transcription units. This important interaction might provide the key to (re-)targeting lentiviral integration and creating safer vectors for gene therapy.
Research themes
- Interactions between retroviral integration machinery and the host
- Cellular functions of LEDGF
- Inhibitors of HIV integrase
- Structural biology of retroviral integration
Recent publications
- Hare S; Gupta SS; Valkov E; Engelman A; Cherepanov P (2010) Retroviral intasome assembly and inhibition of DNA strand transfer. Nature. in press.
- Hughes S; Jenkins V; Dar MJ; Engelman A; Cherepanov P. (2010). Transcriptional Co-activator LEDGF Interacts with Cdc7-Activator of S-phase Kinase (ASK) and Stimulates Its Enzymatic Activity. J. Biol. Chem. 285:541-54.
- Hare S; Di Nunzio F; Labeja A; Wang JM; Engelman A; Cherepanov P. (2009). Structural Basis for Functional Tetramerization of Lentiviral Integrase. PLoS Pathog. 5:e1000515.
- Valkov E; Gupta SS; Hare S; Helander A; Roversi P; McClure M; Cherepanov P. (2009). Functional and structural characterization of the integrase from the prototype foamy virus. Nucleic Acids Res. 37:243-55.
- Hare S; Shun MC; Gupta SS; Valkov E; Engelman A; Cherepanov P. (2009). A novel co-crystal structure affords the design of gain-of-function lentiviral integrase mutants in the presence of modified PSIP1/LEDGF/p75. PLoS Pathog. 5:e1000259.
- Shun MC; Raghavendra NK; Vandegraaff N; Daigle JE; Hughes S; Kellam P; Cherepanov P; Engelman A. (2007). LEDGF/p75 functions downstream from preintegration complex formation to effect gene-specific HIV-1 integration. Genes Dev. 21:1767-78.
