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.
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.
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