PubMed · 11682997
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2000. Consensus statement on long-term effectiveness research.. https://pubmed.ncbi.nlm.nih.gov/11682997/
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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.
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A quantum pharmacological study on nucleosidic inhibitors of HIV-1RT has been performed. The main aim of this study is to discuss the pharmacophoric features (conformational and electrostatic) of nucleosidic inhibitors and compare them with normal substrate dNTP. Present study stresses on the need to refine nucleosidic drugs, as combination therapy to date is still one of the best remedies for AIDS. The results of ab initio HF calculations indicate very little effect of 3' substituent on ring puckering and suggest that potency regulation may be via very intricate phosphate-catalytic triad interactions. Our MESP maps also show charge complementarity between the drug and receptor.