PubMed · 8999549
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B D Preston. 1997-01-10. Reverse transcriptase fidelity and HIV-1 variation.. https://doi.org/10.1126/science.275.5297.228
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BACKGROUND: HIV proviral sequencing overcomes the limit of plasma viral load requirement by detecting all the 'archived mutations', but the clinical relevance remains to be evaluated. METHODS: We included 25 participants with available proviral sequences (both intact and defective sequences available) and utilized the genotypic sensitivity score (GSS) to evaluate the level of resistance in their provirus and plasma virus. Defective sequences were further categorized as sequences with and without hypermutations. Personalized GSS score and total GSS score were calculated to evaluate the level of resistance to a whole panel of antiretroviral therapies and to certain antiretroviral therapy that a participant was using. The rate of sequences with drug resistance mutations (DRMs) within each sequence compartment (intact, defective and plasma viral sequences) was calculated for each participant. RESULTS: Defective proviral sequences harbored more DRMs than other sequence compartments, with a median DRM rate of 0.25 compared with intact sequences (0.0, P = 0.014) and plasma sequences (0.095, P = 0.30). Defective sequences with hypermutations were the major source of DRMs, with a median DRM rate of 1.0 compared with defective sequences without hypermutations (0.042, P < 0.001). Certain Apolipoprotein B Editing Complex 3-related DRMs including reverse transcriptase gene mutations M184I, E138K, M230I, G190E and protease gene mutations M46I, D30N were enriched in hypermutated sequences but not in intact sequences or plasma sequences. All the hypermutated sequences had premature stop codons due to Apolipoprotein B Editing Complex 3. CONCLUSION: Proviral sequencing may overestimate DRMs as a result of hypermutations. Removing hypermutated sequences is essential in the interpretation of proviral drug resistance testing.
As long as the threat of human immunodeficiency virus (HIV) protease drug resistance still exists, there will be a need for more potent antiretroviral agents. We have therefore determined the crystal structures of HIV-1 protease in complex with six cyclic urea inhibitors: XK216, XK263, DMP323, DMP450, XV638, and SD146, in an attempt to identify 1) the key interactions responsible for their high potency and 2) new interactions that might improve their therapeutic benefit. The structures reveal that the preorganized, C2 symmetric scaffolds of the inhibitors are anchored in the active site of the protease by six hydrogen bonds and that their P1 and P2 substituents participate in extensive van der Waals interactions and hydrogen bonds. Because all of our inhibitors possess benzyl groups at P1 and P1', their relative binding affinities are modulated by the extent of their P2 interactions, e.g. XK216, the least potent inhibitor (Ki (inhibition constant) = 4.70 nM), possesses the smallest P2 and the lowest number of P2-S2 interactions; whereas SD146, the most potent inhibitor (Ki = 0.02 nM), contains a benzimidazolylbenzamide at P2 and participates in fourteen hydrogen bonds and approximately 200 van der Waals interactions. This analysis identifies the strongest interactions between the protease and the inhibitors, suggests ways to improve potency by building into the S2 subsite, and reveals how conformational changes and unique features of the viral protease increase the binding affinity of HIV protease inhibitors.
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