The future of integrase inhibitors of HIV-1

Integration of the HIV-1 DNA is required and essential to maintain the viral DNA in the infected cell. Integration process occurs in several events, mainly endonucleolytic processing of the 3′ ends of the viral DNA and strand transfer or joining of the viral and cellular DNA. The design and discovery of integrase inhibitors were first focused at targeting the catalytic site of IN with a specific effect on strand transfer. Several integrase inhibitors were developed clinically, two first generation inhibitors, raltegravir and elvitegravir and then two second-generation inhibitors, dolutegravir and MK-2058. Recently, allosteric integrase inhibitors intended to interfere with the integrase-LEDGF/p75 interaction have been designed. These new inhibitors called LEDGINs have an effect on 3′ processing and strand transfer. Thus, integrase inhibitors present a real added value in combined treatment for naive and experienced HIV infected patients. Combination experiments of LEDGINs and raltegravir suggest that these inhibitors could act additively despite sharing the same viral target. Future therapy could involve combinations of inhibitors of IN function acting though different binding pockets within IN. The place of this class on HIV inhibitors and their future role in perspective of novel therapies to eliminate latent HIV reservoirs and infection for cure should also be explored.

► INSTIs are inhibitors of HIV integration that target the catalytic site of integrase. ► INSTIs of first generation have a relative low genetic barrier to resistance. ► Second generation INSTIs showed different resistance profiles than first generation. ► LEDGINs allosteric inhibitors target interaction between LEDGF/p75 and integrase. ► Allosteric inhibitors could be used in combination with INSTIs.