PubMed · 12240886
The source did not provide an abstract. Follow the original record for more information.
Explore connections, maps & timelines
2000. Sex differences trial started.. https://pubmed.ncbi.nlm.nih.gov/12240886/
Cite the original work for its findings. Save a collection to share your selection of sources.
KEEP EXPLORING
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.
Explore the source record for details and available documents.
We have previously demonstrated that tetrahedral bis(cyclopentadienyl)vanadium(IV) complexes and square pyramidal oxovanadium(IV) complexes of vanadium are rapid and selective spermicidal agents at low micromolar concentrations. This study investigated the potential utility of oxovanadium in combination with thiourea non-nucleoside inhibitors (NNIs) of HIV-1 reverse transcriptase (RT) for the development of an effective dual-function anti-HIV spermicide. Two rationally designed substituted phenyl-ring containing pyridyl thiourea NNIs, N-[2-(2-chlorophenethyl)]-N(')-[2-(5-bromopyridyl)-thiourea) [1] and N-[2-(2-methoxyphenethyl)]-N(')-[2-(pyridyl)-thiourea [2] that exhibited subnanomolar IC(50) values against the drug-sensitive, drug-resistant, and multidrug-resistant strains of HIV-1, were complexed with oxovanadium. The oxovanadium-thiourea [OVT] NNIs, C(29)H(27)Br(2)Cl(2)N(6)O(2)S(2)V [3], and C(31)H(35)N(6)O(4)S(2)V [4], were synthesized by reacting VOSO(4), a V(IV) compound, with the corresponding deprotonated thiourea NNI compounds as ligands. Elemental analysis showed that each OVT-NNI used two thiourea molecules as ligands. The existence of the Vz.dbnd6;O bond (968cm(-1)) was confirmed by IR spectroscopy. No d-d bands were observed in the visible spectra of OVT-NNIs and their EPR spectra were featureless, indicating that the vanadium centers were oxidized to V(V). The new OVT-NNIs as well as their thiourea NNI ligands were evaluated for (i) anti-HIV activity using the cell-free recombinant RT inhibition assays, (ii) cellular HIV replication assays, (iii) spermicidal activity against human sperm by computer-assisted sperm analysis (CASA), and (iv) cytotoxicity against normal human female genital tract epithelial cell using MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) dye-reduction assays. Similar to thiourea NNIs 1 and 2, the OVT-NNIs 3 and 4, exhibited potent anti-HIV activity with submicromolar IC(50[p24]) values (0.08 and 0.128 microM, respectively) and submicromolar IC(50[RT]) values (2.1 and 0.87 microM, respectively). Notably, OVT-NNIs were spermicidal against human sperm at low micromolar concentrations (IC(50)=34 and 55 microM, respectively) and induced rapid sperm immobilization (T(1/2)=12 and 240s) when compared with their respective thiourea NNI ligands (EC(50)=>400 microM and T(1/2)=>180min). Moreover, OVT-NNIs displayed high selectivity indices against normal female genital tract epithelial cells (IC(50) values >250 microM) when compared to the detergent-type spermicide, nonoxynol-9, which was cytotoxic at spermicidal concentrations (IC(50) values 32-64 microM). This is the first report on the dual anti-HIV and spermicidal activities of a vanadium/oxovanadium complex. Our discovery of potent anti-HIV and rapid spermicidal activities of OVT-NNIs may be useful for the development of an effective and safe vaginal anti-HIV spermicide for women who are at high risk for acquiring HIV/AIDS by heterosexual transmission.