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Journal of Virology, October 2005, p. 12584-12591, Vol. 79, No. 19
0022-538X/05/$08.00+0     doi:10.1128/JVI.79.19.12584-12591.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Lys-34, Dispensable for Integrase Catalysis, Is Required for Preintegration Complex Function and Human Immunodeficiency Virus Type 1 Replication

Richard Lu, Nick Vandegraaff, Peter Cherepanov, and Alan Engelman*

Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute, and Department of Pathology, Harvard Medical School, Boston, Massachusetts 02115

Received 13 May 2005/ Accepted 5 July 2005

Retroviral integrases (INs) function in the context of preintegration complexes (PICs). Two conserved Lys residues in the N-terminal domain of human immunodeficiency virus type 1 (HIV-1) IN were analyzed here for their roles in integration and virus replication. Whereas HIV-1K46A grew like the wild type, HIV-1K34A was dead. Yet recombinant INK34A protein functioned in in vitro integration assays, and Vpr-INK34A efficiently transcomplemented the infectivity defect of an IN active site mutant virus in cells. HIV-1K34A was therefore similar to a number of previously characterized mutant viruses that failed to replicate despite encoding catalytically competent IN. To directly analyze mutant PIC function, a sensitive PCR-based integration assay was developed. HIV-1K34A and related mutants failed to support detectable levels (<1% of wild type) of integration. We therefore concluded that mutations like K34A disrupted higher-order interactions important for PIC function/maturation compared to the innate catalytic activity of IN enzyme.

* Corresponding author. Mailing address: Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute, 44 Binney Street, Boston, MA 02115. Phone: (617) 632-4361. Fax: (617) 632-3113. E-mail: alan_engelman{at}dfci.harvard.edu.

Journal of Virology, October 2005, p. 12584-12591, Vol. 79, No. 19
0022-538X/05/$08.00+0     doi:10.1128/JVI.79.19.12584-12591.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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