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Lys-34, dispensable for integrase catalysis, is required for preintegration complex function and human immunodeficiency virus type 1 replication.

Lu R, Vandegraaff N, Cherepanov P, Engelman A

Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute, 44 Binney Street, Boston, MA 02115, USA.

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-1(K46A) grew like the wild type, HIV-1(K34A) was dead. Yet recombinant IN(K34A) protein functioned in in vitro integration assays, and Vpr-IN(K34A) efficiently transcomplemented the infectivity defect of an IN active site mutant virus in cells. HIV-1(K34A) 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-1(K34A) 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.

Published 14 September 2005 in J Virol, 79(19): 12584-91.
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