Why do you think your paper is highly cited?

To date, several combinations of anti-HIV drugs dramatically reduce mortality in HIV-infected patients. However, a complete eradication of HIV has not yet been achieved. The residual replication of HIV allows the emergence of drug-resistant HIV variants, resulting in attenuation of their efficacy. Moreover, some resistant variants acquire cross and/or multi-drug resistance to the same drug classes. Therefore, drug development for HIV therapy appears to be a hot research area both for medical research and society.

One of the essential HIV enzymes, integrase, which integrates the HIV DNA genome into host DNA, is a new attractive target for drug development (see Figure 1 to the right). We describe mechanisms of action and resistance to an HIV integrase inhibitor, elvitegravir, currently in the phase III clinical trial by Gilead Sciences Inc. (Foster City, NC) that appears to be ideal for anti-HIV therapy. Therefore, our paper may help lead to novel anti-HIV drugs for both basic and clinical researchers.

Does it describe a new discovery, methodology, or synthesis of knowledge?

In the paper, we present a new discovery, a profile of elvitegravir through its mechanism of action and resistance. Elvitegravir shows strong anti-HIV activity, even with multi-drug resistance, indicating that it may suppress replication of resistant HIV, which is hardly blocked by previous anti-HIV drugs, such as inhibitors for reverse transcriptase and protease.

Would you summarize the significance of your paper in layman's terms?

Integration is one of the essential steps to complete HIV infection and provides the subsequent production of progeny viruses from infected cells. Elvitegravir effectively inhibits integration of drug-resistant as well as wild-type HIV. Moreover, it blocks integration of various retroviruses, including other animal retroviruses. Elvitegravir seems to bind to the conformationally conserved region of integrase and suppresses the enzymatic activity. To acquire resistance, at least several mutations with severe replication cost were needed. These results suggest that elvitegravir is expected to exert long-lasting efficacy in HIV-infected patients.

How did you become involved in this research, and were there any problems along the way?

This project was begun in 2001 and is a collaboration of Kyoto University (Kyoto, Japan) and the Japan Tobacco Inc., Central Pharmaceutical Research Institute (Osaka, Japan). One of my friends, Dr. Wataru Watanabe, who was affiliated with Japan Tobacco Inc., asked me to participate in the collaboration, since we had previously focused on anti-HIV drug screenings and characterization of the drug-resistant HIV variants.

Drs. Wataru Watanabe and Kazunobu Yamataka from Japan Tobacco Inc. extensively screened their huge compound-library. We spent over three years identifying effective lead compounds and another year to obtain in vitro resistant variants.

Merely to initiate the experiments reported in the paper, considerable time and effort has already been employed. Even though it was quite uncertain whether we could develop excellent compounds, all collaborators listed, and even those unlisted in the paper, extensively and aggressively synthesized and screened these compounds. Therefore, I extend my deepest thanks to each and every one of our collaborators.

Where do you see your research leading in the future?

We have successfully provided the possibility of the development of novel drugs to HIV integrase. Therefore, development of further integrase inhibitors and research on these inhibitors will be accelerated. It may contribute to further suppression of HIV replication in patients.

Do you foresee any social or political implications for your research?

This compound is a once-daily administered, no cross-resistance to at least inhibitors for reverse transcriptase and protease, indicating that it will be quite beneficial to HIV-infected patients. Novel target-oriented compounds, such as integrase inhibitors, may one day enable the long-lasting suppression of HIV replication across a wide range of patients.

Eiichi N. Kodama
Assistant Professor
Laboratory of Virus Control
Institute for Virus Research
Kyoto University
Kyoto, Japan
Web

Keywords: HIV-1 INTEGRASE; REVERSE-TRANSCRIPTASE; PROTEASE INHIBITORS; DNA INTEGRATION; IN-VITRO; MOLECULAR-MECHANISMS; EXPERIENCED PATIENTS; POTENT INHIBITORS; VIRAL REPLICATION; MONONUCLEAR-CELLS.