HIV Drug Resistance and the Advent of Integrase Inhibitors

This review focuses on the topic of HIV integrase inhibitors that are potent antiretroviral drugs that efficiently decrease viral load in patients. However, emergence of resistance mutations against this new class of drugs represents a threat to their long-term efficacy. Here, we provide new information about the most recent mutations identified and other mutations that confer resistance to several integrase inhibitors, such as new resistance mutations-for example, G118R, R263K, and S153Y-that have been identified through in vitro selection studies with second-generation integrase strand transfer inhibitors (INSTIs). These add to the three main resistance pathways involving mutations at positions Y143, N155, and Q148. Deep sequencing, structural modeling, and biochemical analyses are methods that currently help in the understanding of the mechanisms of resistance conferred by these mutations. Although the new resistance mutations appear to confer only low levels of cross-resistance to second-generation drugs, the Q148 pathway with numerous secondary mutations has the potential to significantly decrease susceptibility to all drugs of the INSTI family of compounds.