Antiretroviral therapy does not block the secretion of the human immunodeficiency virus tat protein.

Tat is a viral protein secreted from HIV infected cells and extra cellular Tat is suspected to prevent destruction of HIV infected cells from cells of the cellular immunity. The effect of anti retroviral therapy (ART) on Tat secretion has never been investigated. In this study, we tested for antibody reactivity against Tat variants representative of the main HIV subtypes in HIV positive patients receiving ART with undetectable viral loads ( < 40 copies/mL) over the course of one year with a blood sampling every three months. For each of theses five blood sampling, an average of 50 % of patients had Anti-Tat IgG, it turned out that 86% of patients could recognize Tat at least in one blood sampling during the course of the study. Amazingly, anti-Tat IgG appeared and/or disappeared in 66 % of patients. Only 20% had anti-Tat IgG remaining persistently while 14% were consistently without anti Tat IgG in the five blood sampling. No significant correlation was found between anti-Tat IgG and CD4+ T cell, CD8+ T cell and B cell counts revealing the incapacity of these anti Tat IgG to neutralize extra cellular Tat. Interestingly the absence and then the appearance of anti-Tat IgG in patients suggest the presence of HIV infected cells in the blood that may constitute a significant reservoir of HIV infected cells. As a conclusion antiretroviral therapy does not block the secretion of Tat and may explain why HIV infected cells can survive in spite of an effective ART treatment.

Nitrobenzoxadiazoles and related heterocycles: a relationship between aromaticity, superelectrophilicity and pericyclic reactivity.

A study of the dual electrophilic and pericyclic reactivity of 4,6-dinitrobenzofurazan (DNBZ, 2), 4,6-dinitro-2,1,3-benzothiadiazole (DNBS, 3), 4,6-dinitro-2,1,3-benzoselenadiazole (DNBSe, 4) is reported. Kinetic and thermodynamic measurements of the ease of covalent hydration of 2-4 to give the corresponding hydroxy sigma-adducts C-2-C-4 have been carried out over a large pH range in aqueous solution. Analysis of the data has allowed a determination of the rate constants k1(H2O) pertaining to the susceptibility of 2-4 to water attack as well as the pKa values for the sigma-complexation processes. With pKa values ranging from 3.92 for DNBZ to 6.34 for DNBSe to 7.86 for DNBS, the electrophilic character of the three heteroaromatics is much closer to that of the superelectrophilic reference, i.e. 4,6-dinitrobenzofuroxan (DNBF, 1; pKa = 3.75), than that of the standard Meisenheimer electrophile 1,3,5-trinitrobenzene (TNB, pKa = 13.43). Most importantly, water is found to be an efficient nucleophile which contributes strongly to the formation of the adducts C-2 and C-4. This confirms a previous observation that a pKa value of ca. 8 is a primary requirement for having H2O competing effectively as a nucleophile with OH- in the formation of hydroxy sigma-adducts. On the other hand, 2-4 are found to exhibit dienophilic and/or heterodienic behaviour on treatment with isoprene, 2,3-dimethylbutadiene, cyclopentadiene or cyclohexadiene, affording Diels-Alder mono- or di-adducts which have all been structurally characterized. A major finding is that the order of Diels-Alder reactivity follows clearly the order of electrophilicity, pointing to a direct relationship between superelectrophilic and pericyclic reactivity. This relationship is discussed.

Severe transient neutropenia associated with acute human immunodeficiency virus type 1 infection.

Severe neutropenia associated with primary HIV infection is unusual. We report the fifth case in a 50-year-old male with a neutrophil count of 500/mm(3) and a platelet count of 92,000/mm(3) at the time of early HIV-1 seroconversion. In all previously published cases and in our case, severe neutropenia was a very early sign of acute HIV infection, and it regressed spontaneously and quickly. HIV testing should be recommended when severe neutropenia is observed, especially in the context of a flu-like or mononucleosis-like infectious syndrome.

Therapeutic drug monitoring of lopinavir/ritonavir given alone or with a non-nucleoside reverse transcriptase inhibitor.

AIMS: To evaluate the interindividual variability in the plasma concentrations of lopinavir in the context of routine monitoring with or without treatment with a non-nucleoside reverse transcriptase inhibitor and to assess the interaction between the coformulation of lopinavir/ritonavir and efavirenz or nevirapine. METHODS: Plasma trough and peak concentrations (C(trough), C(max)) of lopinavir from 182 HIV-1-infected patients were analysed by high-performace liquid chromatography. Three lopinavir/ritonavir regimens were assessed, namely (A) 400 mg lopinavir/100 mg ritonavir twice daily given alone (n = 125), (B) 400/100 mg twice daily together with a non-nucleoside reverse transcriptase inhibitor (n = 25), and (C) 533/133 mg twice daily together with a non-nucleoside reverse transcriptase inhibitor (n = 32). RESULTS: Median (ng ml(-1)) C(trough) and C(max) lopinavir (interquartile range, CV) were: (A) 4852 (3198-6891, 56%) and 8501 (6333-11 584, 41%), (B) 2979 (1704-5186, 74%) and 5612 (3362-11 704, 76%) and (C) 5082 (2696-7226, 74%) and 9757 (4883-12 963, 60%). Median C(trough) of lopinavir was lower in patients taking both efavirenz [P = 0.01, 95% confidence interval (CI) for difference between medians 343, 2713] and nevirapine (P = 0.019, 95% CI for difference between medians 354, 3681) compared with those taking lopinavir/ritonavir alone. A higher interindividual variability was observed when lopinavir/ritonavir was given with a non-nucleoside reverse transcriptase inhibitor. The risk of achieving a 'suboptimal'C(trough) of lopinavir (below a threshold of 3000 ng ml(-1)) was statistically higher in patients treated with a non-nucleoside reverse transcriptase inhibitor (P < 0.001, 95% CI for difference between percentages 8.8, 43.1%) compared with those receiving lopinavir/ritonavir alone. CONCLUSIONS: Our results confirmed the interaction between lopinavir and efavirenz, and also demonstrated a significant interaction between the former drug and nevirapine, resulting in lower C(trough) of lopinavir. The wide interpatient variability in this interaction suggests that therapeutic drug monitoring may be useful in optimizing the dose of lopinavir.

High Brønsted beta nuc values in SNAr displacement. An indicator of the SET pathway?

Nucleophilic substitutions of 4-chloro-7-nitrobenzofurazan (NBD-Cl) and 3-methyl-1-(4-nitrobenzofurazanyl)-imidazolium ions (NBD-Im+) with a series of 4-X-substituted anilines have been kinetically investigated in 70-30 (v/v) and 20-80 (v/v) H2O-Me2SO mixtures. The rate-limiting step in these reactions is nucleophilic addition with formation of Meisenheimer-type sigma-adducts followed by fast expulsion of the leaving group (Cl- or Im). The reactions are characterized by a notable sensitivity to basicity of the aniline nucleophiles, with Hammett rho values of -2.68 and -3.82 in 30% and 80% Me2SO, respectively, for NBD-Cl and even more negative values, -3.43 and -5.27, respectively, for NBD-Im+. This is consistent with significant development of positive charge at the nitrogen atom of the zwitterionic sigma-adduct. Unexpectedly, the Brønsted-type plots reveal abnormally high beta nuc values, ca. 1.0 and 1.3-1.4, respectively. Satisfactory correlations between the rates of the reactions and the oxidation potentials of the respective anilines support a SET mechanism for this process, i.e. initial (fast) electron-transfer from the aniline donor to the nitrobenzofurazan acceptor moiety and subsequent (slow) coupling of the resulting cation and anion radicals within the solvent cage with formation of the sigma-adduct. An alternative possible explanation of the high beta nuc values being related to the strong--I effect exerted by the negatively charged 4-nitrobenzofurazanyl structure, which would induce a greater positive charge at the developing anilinium nitrogen atom in the sigma-adduct-like transition state as compared with the situation in the reference protonation equilibria of anilines, is considered less probable. It is thus proposed that obtention of abnormal beta nuc values may be an indicator of electron-transfer in nucleophilic aromatic substitution and highlights the transition from the polar (SNAr) to the single electron-transfer (SET) mechanism.