Integration of human immunodeficiency virus as a target for antiretroviral therapy

Most of the studies investigating inhibition of human immunodeficiency virus integration have focused on blocking the enzymatic functions of HIV integrase, with the predominant judgment that integration inhibitors need to block at least one of the integrase-catalyzed reactions. Recent studies, however, have highlighted the importance of other proteins and their contacts with integrase in the preintegration complex, and their involvement in chromosomal integration of the viral DNA.

Promising results of clinical trials for two new integrase inhibitors were announced recently, providing the proof of the concept for using HIV-1 integrase inhibitors as antiretroviral therapy. Two strategies are currently employed for the development of novel inhibitors of HIV integrase: synthesis of hybrid molecules comprising core structures of two or more known inhibitors, and three-dimensional pharmacophore searches based on previously discovered compounds. By highlighting the role of the cellular cofactor LEDGF/p75 in HIV integration, novel approaches are indicated that aim to develop compounds altering contact between HIV integrase and integration cofactors.

By the discovery of novel inhibitors and targets for HIV integration, coupled with recent studies in characterizing preintegration complex formation, new insight is provided for the rational design of anti-HIV integration inhibitors.