HIV integrase inhibitors: 20-year landmark and challenges.

Since the discovery of HIV as the cause for AIDS 30 years ago, major progress has been made, including the discovery of drugs that now control the disease. Here, we review the integrase (IN) inhibitors from the discovery of the first compounds 20 years ago to the approval of two highly effective IN strand transfer inhibitors (INSTIs), raltegravir (Isentress) and elvitegravir (Stribild), and the promising clinical activity of dolutegravir. After summarizing the molecular mechanism of action of the INSTIs as interfacial inhibitors, we discuss the remaining challenges. Those include: overcoming resistance to clinical INSTIs, long-term safety of INSTIs, cost of therapy, place of the INSTIs in prophylactic treatments, and the development of new classes of inhibitors (the LEDGINs) targeting IN outside its catalytic site. We also discuss the role of chromatin and host DNA repair factor for the completion of integration.