PubMed · 11851144
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B Garcia. 2000. I will urge caution.. https://pubmed.ncbi.nlm.nih.gov/11851144/
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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.
Tetrahydroimidazo-[4,5,l-jk][1,4]-benzodiazepin-2-(1H)-one (TIBO) derivatives are important nonnucleoside human immunodeficiency virus-1 reverse transcriptase inhibitors (NNRTI). Several TIBO derivatives have shown high potency to inhibit reverse transcriptase (RT) and one (Tivirapine) has entered into clinical trials. The free energy of binding (FEB) is a numerical way to express the binding affinity of a ligand to its receptor and has been applied in screening candidates in rational drug design. In this work, the FEB of 42 TIBOs in RT was studied. Relative FEB is expressed in the form of a linear combination of vdW, electrostatic, solvation, and nonpolar solvation energy terms. The predicted FEB activity of the TIBOs studied has a good correlation (r(2) = 0.8680, q(2) = 0.8298) with respect to the experimental activity (pIC(50)). Based on the data reported here, the Finite Difference Poisson Boltzmann with a Gaussian Smooth Dielectric Constant Function method (PB/GS) solvation energy term is very important in predicting the binding affinity of TIBOs in RT. In summary, the Dock-Molecular Mechanics (MM)-PB/GS method is a promising technique in predicting ligand/receptor binding affinity and it can be used to screen relatively large sets of molecules in a reasonable amount of computer time.
We found that indolicidin, a natural antimicrobial peptide, has HIV-1 integrase inhibitory activity. Subsequently, we also discovered analogs of indolicidin with substantially higher inhibitory potency. The dimers and tetramers of the most active sequence (ILPWKWPWWPWPP) were prepared by connection of the monomers' C-terminal ends, using lysine as a linker. The inhibitory potency of the dimeric peptide is higher than the monomeric peptide. The tetrameric peptide, prepared by connection of two dimers at C-ends using again lysine as the linker, is the most potent integrase inhibitor with IC(50) value of 0.6 microM for both 3'-end processing and strand transfer.