Integrase strand transfer inhibitors (INSTIs) like dolutegravir are preferred first-line ART components. Their mechanism of action involves:

• A Blocking HIV protease, preventing cleavage of Gag-Pol polyprotein into functional enzymes
• B Binding the NNRTI pocket of HIV reverse transcriptase, inducing a conformational change
• C Blocking HIV integrase binding to the viral long terminal repeat (LTR) sequences
• D Chelating magnesium ions in the HIV integrase active site, preventing strand transfer of viral DNA into host chromosomal DNA ✓

Explanation

HIV integrase catalyzes two sequential reactions: 3'-processing (removing two nucleotides from each viral DNA end) and strand transfer (inserting the processed viral DNA into host chromosomal DNA). INSTIs (raltegravir, elvitegravir, dolutegravir, bictegravir) specifically inhibit the strand transfer step by chelating two Mg2+ ions in the integrase active site, which are essential for catalysis. This prevents covalent insertion of HIV cDNA into the host genome. Dolutegravir has a higher genetic barrier to resistance due to its slower dissociation from integrase.

Reference: KD Tripathi, Essentials of Medical Pharmacology, 8th ed.

High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP

Written and medically reviewed by the StethoPrep medical team.