Inhibitors of human immunodeficiency virus type I integration

The virally encoded enzyme integrase plays a critical role in HIV-1 replication and has long been considered a promising target for the development of agents to treat HIV-1 infection. It is only recently, however, that the efficacy of integrase inhibitors has been demonstrated in experimental animal model systems of retroviral infection, and in HIV-1 infected subjects. Several compounds that have shown potent efficacy in short-term monotherapy studies have initiated phase two and three clinical studies in 2006.

Although the first inhibitors in this new class of antiretroviral therapy are in the earliest stages of clinical development, the study of integrase function and inhibitor mechanism, as well as recent insights on resistance to prototypical inhibitors in vitro, have important implications for the discovery and development of these agents.

This review will summarize the role of integrase in HIV-1 infection, the mechanism of integrase inhibitors, and the results of resistance studies on preclinical compounds which suggest there may be multiple opportunities for developing inhibitors against this essential HIV-1 target.