Molecular mechanisms in retrovirus DNA integration

Abstract

The integrase protein of retroviruses catalyzes the insertion of the viral DNA into the genomes of the cells that they infect. Integrase is necessary and sufficient for this recombination reaction in vitro; however, the enzyme's activity appears to be modulated in vivo by viral and cellular components included in the nucleoprotein pre-integration complex. In addition to integrase, cis-acting sequences at the ends of the viral DNA are important for integration. Solution of the structures of the isolated N- and C-terminal domains of HIV-1 integrase by nuclear magnetic resonance (NMR) and the available crystal structures of the catalytic core domains from human immunodeficiency virus type-1 (HIV-1) and avian sarcoma virus (ASV) integrases are providing a structural basis for understanding some aspects of the integration reaction. The role of the evolutionarily conserved acidic amino acids in the D,D(35)E motif as metal-coordinating residues that are critical for catalysis, has been confirmed by the metal-integrase (core domain) complexes of ASV integrase. The central role that integrase plays in the life cycle of the virus makes it an attractive target for the design of drugs against retroviral diseases such as AIDS. To this end, several compounds have been screened for inhibitory effects against HIV-1 integrase. These include DNA intercalators, peptides, RNA ligands, and small organic compounds such as bis-catechols, flavones, and hydroxylated arylamides. Although the published inhibitors are not very potent, they serve as valuable leads for the development of the next generation of tight-binding analogues that are more specific to integrase. In addition, new approaches are being developed, exemplified by intracellular immunization studies with conformation-sensitive inhibitory monoclonal antibodies against HIV-1 integrase. Increased knowledge of the mechanism of retroviral DNA integration should provide new strategies for the design of effective antivirals that inhibit integrase in the future.