Dolutegravir (DTG) has a higher genetic barrier to HIV resistance than raltegravir and elvitegravir. Which molecular feature of dolutegravir's integrase binding explains this?

• A DTG is not a substrate for P-glycoprotein efflux unlike raltegravir
• B DTG binds integrase more deeply into the active site with broader molecular contacts (including Thr66 and Val75) and a slower dissociation rate, requiring two simultaneous mutations for resistance that come with high fitness cost ✓
• C DTG inhibits both integrase strand transfer and 3'-processing steps, unlike raltegravir which only inhibits strand transfer
• D DTG covalently binds the integrase active site magnesium ions, making resistance mutations impossible

Explanation

All three INSTIs (raltegravir, elvitegravir, dolutegravir) inhibit HIV integrase strand transfer by chelating the two magnesium ions in the active site. Dolutegravir's higher genetic barrier arises from its unique binding mode: it has a larger footprint within the integrase active site with additional hydrogen bonds and hydrophobic contacts at Thr66, Val75, and surrounding residues. The single Q148H/K/R mutations that confer high-level raltegravir resistance reduce DTG susceptibility only minimally. For clinically significant DTG resistance, at least two specific mutations at positions 138, 148, or 155 are required simultaneously — and these dual mutations impose a severe replication fitness cost on the virus, making DTG resistance rare in treatment-naive patients.

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

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