Targeting HIV-1 integrase: A review of options, challenges and future directions

HIV-1 infects CD4⁺ T-cells, causing immunodeficiency and, if untreated, progression to AIDS. Global antiretroviral therapy scale-up has reduced deaths and new infections by nearly half over the past decade, yet lifelong treatment and emerging drug resistance remain critical challenges. This review provides an overview of the HIV-1 lifecycle, with emphasis on the structure, function, and multiple roles of IN in viral replication. We discuss the development, mechanisms of action, clinical utility, and resistance profiles of current integrase inhibitors, underscoring the need for innovative approaches to drug discovery. Emerging strategies that exploit non-catalytic functions of integrase are critically evaluated as promising avenues for overcoming resistance and expanding the antiviral repertoire. The biochemical, biophysical, and cell-based screening platforms that have enabled integrase inhibitor discovery and continue to drive next-generation drug development are examined as a critical component of the integrase drug discovery ecosystem. Recent advances in assay technologies, structural biology, and computational approaches are highlighted for their potential to expand the integrase-targeting therapeutic arsenal and address the growing challenge of antiviral resistance.