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A more recent version of this article appeared on February 17, 2006 Originally published In Press as doi:10.1074/jbc.M510628200 on December 9, 2005
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Papers In Press, published online ahead of print November 18, 2005
J. Biol. Chem, 10.1074/jbc.M510628200
Submitted on September 28, 2005
Revised on November 16, 2005
Accepted on November 18, 2005

Identification of amino acids in HIV-1 and ASV integrase subsites required for specific recognition of the LTR termini

Aiping Chen, Irene T. Weber, Robert Harrison, and Jonathan Leis

Microbiology and Immunology, Northwestern University School of Medicine, Chicago, IL 60611

Corresponding Author: j-leis{at}northwestern.edu

A tetramer model for HIV-1 IN with DNA representing 20 bp of the U3 and U5 LTR termini was assembled using structural and biochemical data and molecular dynamics simulations. It predicted amino acid residues on the enzyme surface that can interact with the LTR termini. A separate structural alignment of HIV-1, SIV, and ASV INs predicted which of these residues were unique. To determine if these residues were responsible for specific recognition of the LTR termini, the amino acids from ASV IN were substituted into the structurally equivalent positions of HIV-1 IN and the ability of the chimeras to 3’ process U5 HIV-1 or ASV duplex oligos was determined. This analysis demonstrated that there are multiple amino acid contacts with the LTRs and that substitution of ASV IN amino acids at many of the analogous positions in HIV-1 IN conferred partial ability to cleave ASV substrates with a concomitant loss in the ability to cleave the homologous HIV-1 substrate. HIV-1 IN residues that changed specificity include V72, S153, K160-I161, G163-V165, and H171-L172. Because a chimera that combines several of these substitutions shows a specificity of cleavage of the U5 ASV substrate closer to wild type ASV IN compared to chimeras with individual amino acid substitutions, it appears that the sum of the IN interactions with the LTRs determines the specificity. Finally, residues S153 and V72 in HIV-1 IN are among those that change in enzymes that develop resistance to naphthyridine carboxamide and diketo acid related inhibitors in cells. Thus, amino acid residues involved in recognition of the LTRs are at positions that change in development of drug resistance.


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