Non-integrase mechanisms for dolutegravir resistance

Area of Science:

• Virology
• Drug Resistance Mechanisms
• Antiretroviral Therapy

Background:

• Antiretroviral drugs targeting HIV-1 replication have significantly improved global AIDS management.
• Current HIV-1 therapies often combine nucleoside reverse transcriptase inhibitors with second-generation integrase strand transfer inhibitors (INSTIs), such as dolutegravir.

Purpose of the Study:

• To review non-integrase pathways contributing to dolutegravir resistance in HIV-1.
• To discuss the molecular mechanisms underlying these resistance pathways.
• To evaluate the clinical implications of these findings for INSTI drug resistance.

Main Methods:

• Review of laboratory-based research identifying non-integrase resistance pathways.
• Analysis of molecular mechanisms conferring resistance to dolutegravir.
• Discussion of clinical reports of treatment failure in the absence of known integrase mutations.

Main Results:

• HIV-1 exhibits resistance to dolutegravir through non-integrase mechanisms involving viral envelope glycoproteins, nucleocapsid protein, or the genomic RNA polypurine tract.
• These pathways confer resistance via distinct molecular mechanisms.
• Drug resistance mutations in integrase typically confer low-level resistance to both first- and second-generation INSTIs.

Conclusions:

• Multiple non-integrase pathways demonstrate HIV-1's adaptability in circumventing potent antiretroviral drugs like dolutegravir.
• Continued surveillance for specific genetic changes is essential for the safe and effective use of dolutegravir-based therapies.
• These findings underscore the importance of monitoring viral plasticity in HIV-1 treatment.