Non-integrase mechanisms for dolutegravir resistance

Antiretroviral inhibitors that target specific aspects of human immunodeficiency virus 1 (HIV-1) replication have made a huge impact on the management of the global AIDS pandemic and the health and well-being of people that live with HIV. Current maintenance therapies commonly consist of one or two nucleoside reverse transcriptase inhibitors co-formulated with a second-generation integrase strand transfer inhibitor (INSTI), and regimens containing the second-generation INSTI dolutegravir are in wide-use across the globe.

INSTIs are active site inhibitors that block HIV-1 DNA integration- more precisely, the ability of the integrase enzyme to join the 3' ends of the viral reverse transcript with host chromosomal DNA. High-level resistance to first-generation INSTIs readily occurs via amino acid substitutions proximal to the integrase active site. Second-generation INSTIs, by contrast, impart comparatively high genetic barriers to the generation of drug resistance. When observed, such changes within integrase tend to confer comparatively low level resistance to both first- and second-generation INSTIs. Moreover, there are several reports of clinical failure to dolutegravir in the absence of known integrase drug resistance mutations. Laboratory-based research has at the same time identified three non-integrase pathways that can lead to dolutegravir resistance, including changes within the viral surface and transmembrane envelope glycoproteins, the nucleocapsid protein, and the genomic RNA 3' polypurine tract that serves to prime plus-strand DNA synthesis during reverse transcription. Each type of change has been shown to confer resistance to dolutegravir through a unique molecular mechanism. Herein, I review the non-integrase changes that are known to occur and the proposed mechanisms that lead to the generation of dolutegravir resistance. The potential for these different types of changes to impact INSTI drug resistance in the clinic is also discussed.

The unexpected observation that multiple non-integrase pathways can contribute to the generation of dolutegravir resistance highlights the remarkable plasticity of HIV-1 to circumvent challenge with a highly efficacious small molecule inhibitor. Given its current global use as a frontline anti-HIV inhibitor, this research informs regions of sequence surveillance for the continued safe and efficacious use of dolutegravir-based antiretroviral therapies.