HIV-1 Integrase T218I/S Polymorphisms Do Not Reduce HIV-1 Integrase Inhibitors' Phenotypic Susceptibility

Area of Science:

• Virology
• Molecular Biology
• Pharmacology

Background:

• Cabotegravir (CAB) is an FDA-approved antiretroviral for HIV treatment and prevention.
• Integrase natural polymorphisms can compromise CAB efficacy, especially with resistance mutations like G140S/Q148H.
• Increased CAB use for treatment and pre-exposure prophylaxis (PrEP) necessitates understanding resistance implications.

Purpose of the Study:

• To investigate the impact of T218I and T218S polymorphisms on CAB activity.
• To assess the effect of these polymorphisms in combination with G140S/Q148H resistance mutations.
• To evaluate the neutrality of T218I and T218S against other integrase inhibitors.

Main Methods:

• Molecular and cell-based assays were employed.
• Infectivity, integration, and drug resistance were measured.
• The study examined T218I and T218S individually and with G140S/Q148H mutations.

Main Results:

• T218I and T218S did not significantly affect infectivity or integration.
• These polymorphisms did not alter resistance to cabotegravir (CAB).
• T218I and T218S showed neutrality against raltegravir, elvitegravir, and dolutegravir.

Conclusions:

• The T218I and T218S natural polymorphisms are unlikely to compromise CAB effectiveness.
• These findings support the continued use of CAB for HIV treatment and PrEP.
• The study provides crucial data on integrase inhibitor resistance profiles.