A candidate anti-HIV reservoir compound, auranofin, exerts a selective ‘anti-memory' effect by exploiting the baseline oxidative status of lymphocytes
Identifieur interne : 000266 ( Pmc/Checkpoint ); précédent : 000265; suivant : 000267A candidate anti-HIV reservoir compound, auranofin, exerts a selective ‘anti-memory' effect by exploiting the baseline oxidative status of lymphocytes
Auteurs : B. Chirullo [Italie] ; R. Sgarbanti [Italie] ; D. Limongi [Italie] ; I L Shytaj [Italie] ; D. Alvarez [États-Unis] ; B. Das [États-Unis] ; A. Boe [Italie] ; S. Dafonseca [États-Unis] ; N. Chomont [États-Unis] ; L. Liotta [États-Unis] ; E. Iii Petricoin [États-Unis] ; S. Norelli [Italie] ; E. Pelosi [Italie] ; E. Garaci [Italie] ; A. Savarino [Italie] ; A T Palamara [Italie]Source :
- Cell Death & Disease [ 2041-4889 ] ; 2013.
Abstract
Central memory (TCM) and transitional memory (TTM) CD4+ T cells are known to be the major cellular reservoirs for HIV, as these cells can harbor a transcriptionally silent form of viral DNA that is not targeted by either the immune system or current antiretroviral drug regimens. In the present study, we explored the molecular bases of the anti-HIV reservoir effects of auranofin (AF), a pro-oxidant gold-based drug and a candidate compound for a cure of AIDS. We here show that TCM and TTM lymphocytes have lower baseline antioxidant defenses as compared with their naive counterpart. These differences are mirrored by the effects exerted by AF on T-lymphocytes: AF was able to exert a pro-differentiating and pro-apoptotic effect, which was more pronounced in the memory subsets. AF induced an early activation of the p38 mitogen-activated protein kinase (p38 MAPK) followed by mitochondrial depolarization and a final burst in intracellular peroxides. The pro-differentiating effect was characterized by a downregulation of the CD27 marker expression. Interestingly, AF-induced apoptosis was inhibited by pyruvate, a well-known peroxide scavenger, but pyruvate did not inhibit the pro-differentiating effect of AF, indicating that the pro-apoptotic and pro-differentiating effects involve different pathways. In conclusion, our results demonstrate that AF selectively targets the TCM/TTM lymphocyte subsets, which encompass the HIV reservoir, by affecting redox-sensitive cell death pathways.
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DOI: 10.1038/cddis.2013.473
PubMed: 24309931
PubMed Central: 3877546
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Chirullo</name><affiliation wicri:level="1"><nlm:aff id="aff1"><institution>Istituto Superiore di Sanità</institution>, Viale Regina Elena, 299, Rome,<country>Italy</country></nlm:aff><country xml:lang="fr">Italie</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Sgarbanti, R" sort="Sgarbanti, R" uniqKey="Sgarbanti R" first="R" last="Sgarbanti">R. Sgarbanti</name><affiliation wicri:level="1"><nlm:aff id="aff2"><institution>Scientific Institute for Research, Hospitalization and Health Care, Università Telematica San Raffaele</institution>, Rome,<country>Italy</country></nlm:aff><country xml:lang="fr">Italie</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Limongi, D" sort="Limongi, D" uniqKey="Limongi D" first="D" last="Limongi">D. Limongi</name><affiliation wicri:level="1"><nlm:aff id="aff2"><institution>Scientific Institute for Research, Hospitalization and Health Care, Università Telematica San Raffaele</institution>, Rome,<country>Italy</country></nlm:aff><country xml:lang="fr">Italie</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Shytaj, I L" sort="Shytaj, I L" uniqKey="Shytaj I" first="I L" last="Shytaj">I L Shytaj</name><affiliation wicri:level="1"><nlm:aff id="aff1"><institution>Istituto Superiore di Sanità</institution>, Viale Regina Elena, 299, Rome,<country>Italy</country></nlm:aff><country xml:lang="fr">Italie</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Alvarez, D" sort="Alvarez, D" uniqKey="Alvarez D" first="D" last="Alvarez">D. Alvarez</name><affiliation wicri:level="1"><nlm:aff id="aff3"><institution>Department of Molecular Biology and Microbiology, Case Western Reserve University School of Medicine</institution>, Cleveland, OH,<country>USA</country></nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Das, B" sort="Das, B" uniqKey="Das B" first="B" last="Das">B. Das</name><affiliation wicri:level="1"><nlm:aff id="aff3"><institution>Department of Molecular Biology and Microbiology, Case Western Reserve University School of Medicine</institution>, Cleveland, OH,<country>USA</country></nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Boe, A" sort="Boe, A" uniqKey="Boe A" first="A" last="Boe">A. Boe</name><affiliation wicri:level="1"><nlm:aff id="aff1"><institution>Istituto Superiore di Sanità</institution>, Viale Regina Elena, 299, Rome,<country>Italy</country></nlm:aff><country xml:lang="fr">Italie</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Dafonseca, S" sort="Dafonseca, S" uniqKey="Dafonseca S" first="S" last="Dafonseca">S. Dafonseca</name><affiliation wicri:level="1"><nlm:aff id="aff4"><institution>Vaccine and Gene Therapy Institute Florida</institution>, Port St Lucie, FL,<country>USA</country></nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Chomont, N" sort="Chomont, N" uniqKey="Chomont N" first="N" last="Chomont">N. Chomont</name><affiliation wicri:level="1"><nlm:aff id="aff4"><institution>Vaccine and Gene Therapy Institute Florida</institution>, Port St Lucie, FL,<country>USA</country></nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Liotta, L" sort="Liotta, L" uniqKey="Liotta L" first="L" last="Liotta">L. Liotta</name><affiliation wicri:level="1"><nlm:aff id="aff5"><institution>Center for Applied Proteomics and Molecular Medicine, George Mason University</institution>, Manassas, VA,<country>USA</country></nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Iii Petricoin, E" sort="Iii Petricoin, E" uniqKey="Iii Petricoin E" first="E" last="Iii Petricoin">E. Iii Petricoin</name><affiliation wicri:level="1"><nlm:aff id="aff5"><institution>Center for Applied Proteomics and Molecular Medicine, George Mason University</institution>, Manassas, VA,<country>USA</country></nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Norelli, S" sort="Norelli, S" uniqKey="Norelli S" first="S" last="Norelli">S. Norelli</name><affiliation wicri:level="1"><nlm:aff id="aff1"><institution>Istituto Superiore di Sanità</institution>, Viale Regina Elena, 299, Rome,<country>Italy</country></nlm:aff><country xml:lang="fr">Italie</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Pelosi, E" sort="Pelosi, E" uniqKey="Pelosi E" first="E" last="Pelosi">E. Pelosi</name><affiliation wicri:level="1"><nlm:aff id="aff1"><institution>Istituto Superiore di Sanità</institution>, Viale Regina Elena, 299, Rome,<country>Italy</country></nlm:aff><country xml:lang="fr">Italie</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Garaci, E" sort="Garaci, E" uniqKey="Garaci E" first="E" last="Garaci">E. Garaci</name><affiliation wicri:level="1"><nlm:aff id="aff6"><institution>Department of Experimental Medicine and Surgery, University of Rome Tor Vergata</institution>, Rome,<country>Italy</country></nlm:aff><country xml:lang="fr">Italie</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Savarino, A" sort="Savarino, A" uniqKey="Savarino A" first="A" last="Savarino">A. Savarino</name><affiliation wicri:level="1"><nlm:aff id="aff1"><institution>Istituto Superiore di Sanità</institution>, Viale Regina Elena, 299, Rome,<country>Italy</country></nlm:aff><country xml:lang="fr">Italie</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Palamara, A T" sort="Palamara, A T" uniqKey="Palamara A" first="A T" last="Palamara">A T Palamara</name><affiliation wicri:level="1"><nlm:aff id="aff7"><institution>Dept of Public Health and Infectious Diseases, Institute Pasteur Cenci Bolognetti Foundation, Sapienza University of Rome</institution>, Rome,<country>Italy</country></nlm:aff><country xml:lang="fr">Italie</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="aff8"><institution>San Raffaele Pisana Scientific Institute for Research, Hospitalization and Health Care</institution>, Rome,<country>Italy</country></nlm:aff><country xml:lang="fr">Italie</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author></analytic><series><title level="j">Cell Death & Disease</title><idno type="eISSN">2041-4889</idno><imprint><date when="2013">2013</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p>Central memory (T<sub>CM</sub>) and transitional memory (T<sub>TM</sub>) CD4<sup>+</sup> T cells are known to be the major cellular reservoirs for HIV, as these cells can harbor a transcriptionally silent form of viral DNA that is not targeted by either the immune system or current antiretroviral drug regimens. In the present study, we explored the molecular bases of the anti-HIV reservoir effects of auranofin (AF), a pro-oxidant gold-based drug and a candidate compound for a cure of AIDS. We here show that T<sub>CM</sub> and T<sub>TM</sub> lymphocytes have lower baseline antioxidant defenses as compared with their naive counterpart. These differences are mirrored by the effects exerted by AF on T-lymphocytes: AF was able to exert a pro-differentiating and pro-apoptotic effect, which was more pronounced in the memory subsets. AF induced an early activation of the p38 mitogen-activated protein kinase (p38 MAPK) followed by mitochondrial depolarization and a final burst in intracellular peroxides. The pro-differentiating effect was characterized by a downregulation of the CD27 marker expression. Interestingly, AF-induced apoptosis was inhibited by pyruvate, a well-known peroxide scavenger, but pyruvate did not inhibit the pro-differentiating effect of AF, indicating that the pro-apoptotic and pro-differentiating effects involve different pathways. In conclusion, our results demonstrate that AF selectively targets the T<sub>CM</sub>/T<sub>TM</sub> lymphocyte subsets, which encompass the HIV reservoir, by affecting redox-sensitive cell death pathways.</p></div></front><back><div1 type="bibliography"><listBibl><biblStruct><analytic><author><name sortKey="Badley, Ad" uniqKey="Badley A">AD Badley</name></author><author><name sortKey="Sainski, A" uniqKey="Sainski A">A Sainski</name></author><author><name sortKey="Wightman, F" uniqKey="Wightman F">F Wightman</name></author><author><name sortKey="Lewin, Sr" uniqKey="Lewin S">SR Lewin</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Lafeuillade, A" uniqKey="Lafeuillade A">A Lafeuillade</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Remoli, Al" uniqKey="Remoli A">AL Remoli</name></author><author><name sortKey="Marsili, G" uniqKey="Marsili G">G Marsili</name></author><author><name sortKey="Battistini, A" 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<front><journal-meta><journal-id journal-id-type="nlm-ta">Cell Death Dis</journal-id><journal-id journal-id-type="iso-abbrev">Cell Death Dis</journal-id><journal-title-group><journal-title>Cell Death & Disease</journal-title></journal-title-group><issn pub-type="epub">2041-4889</issn><publisher><publisher-name>Nature Publishing Group</publisher-name></publisher></journal-meta><article-meta><article-id pub-id-type="pmid">24309931</article-id><article-id pub-id-type="pmc">3877546</article-id><article-id pub-id-type="pii">cddis2013473</article-id><article-id pub-id-type="doi">10.1038/cddis.2013.473</article-id><article-categories><subj-group subj-group-type="heading"><subject>Original Article</subject></subj-group></article-categories><title-group><article-title>A candidate anti-HIV reservoir compound, auranofin, exerts a selective ‘anti-memory' effect by exploiting the baseline oxidative status of lymphocytes</article-title><alt-title alt-title-type="running">AF exerts a selective anti-memory effect</alt-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>Chirullo</surname><given-names>B</given-names></name><xref ref-type="aff" rid="aff1">1</xref><xref ref-type="author-notes" rid="note1"><sup>9</sup></xref></contrib><contrib contrib-type="author"><name><surname>Sgarbanti</surname><given-names>R</given-names></name><xref ref-type="aff" rid="aff2">2</xref><xref ref-type="author-notes" rid="note1"><sup>9</sup></xref></contrib><contrib contrib-type="author"><name><surname>Limongi</surname><given-names>D</given-names></name><xref ref-type="aff" rid="aff2">2</xref></contrib><contrib contrib-type="author"><name><surname>Shytaj</surname><given-names>I L</given-names></name><xref ref-type="aff" rid="aff1">1</xref></contrib><contrib contrib-type="author"><name><surname>Alvarez</surname><given-names>D</given-names></name><xref ref-type="aff" rid="aff3">3</xref></contrib><contrib contrib-type="author"><name><surname>Das</surname><given-names>B</given-names></name><xref ref-type="aff" rid="aff3">3</xref></contrib><contrib contrib-type="author"><name><surname>Boe</surname><given-names>A</given-names></name><xref ref-type="aff" rid="aff1">1</xref></contrib><contrib contrib-type="author"><name><surname>DaFonseca</surname><given-names>S</given-names></name><xref ref-type="aff" rid="aff4">4</xref></contrib><contrib contrib-type="author"><name><surname>Chomont</surname><given-names>N</given-names></name><xref ref-type="aff" rid="aff4">4</xref></contrib><contrib contrib-type="author"><name><surname>Liotta</surname><given-names>L</given-names></name><xref ref-type="aff" rid="aff5">5</xref></contrib><contrib contrib-type="author"><name><surname>III Petricoin</surname><given-names>E</given-names></name><xref ref-type="aff" rid="aff5">5</xref></contrib><contrib contrib-type="author"><name><surname>Norelli</surname><given-names>S</given-names></name><xref ref-type="aff" rid="aff1">1</xref></contrib><contrib contrib-type="author"><name><surname>Pelosi</surname><given-names>E</given-names></name><xref ref-type="aff" rid="aff1">1</xref></contrib><contrib contrib-type="author"><name><surname>Garaci</surname><given-names>E</given-names></name><xref ref-type="aff" rid="aff6">6</xref><xref ref-type="author-notes" rid="note1"><sup>9</sup></xref></contrib><contrib contrib-type="author"><name><surname>Savarino</surname><given-names>A</given-names></name><xref ref-type="aff" rid="aff1">1</xref><xref ref-type="author-notes" rid="note1"><sup>9</sup></xref><xref ref-type="corresp" rid="caf1">*</xref></contrib><contrib contrib-type="author"><name><surname>Palamara</surname><given-names>A T</given-names></name><xref ref-type="aff" rid="aff7">7</xref><xref ref-type="aff" rid="aff8">8</xref><xref ref-type="author-notes" rid="note1"><sup>9</sup></xref></contrib><aff id="aff1"><label>1</label><institution>Istituto Superiore di Sanità</institution>, Viale Regina Elena, 299, Rome,<country>Italy</country></aff><aff id="aff2"><label>2</label><institution>Scientific Institute for Research, Hospitalization and Health Care, Università Telematica San Raffaele</institution>, Rome,<country>Italy</country></aff><aff id="aff3"><label>3</label><institution>Department of Molecular Biology and Microbiology, Case Western Reserve University School of Medicine</institution>, Cleveland, OH,<country>USA</country></aff><aff id="aff4"><label>4</label><institution>Vaccine and Gene Therapy Institute Florida</institution>, Port St Lucie, FL,<country>USA</country></aff><aff id="aff5"><label>5</label><institution>Center for Applied Proteomics and Molecular Medicine, George Mason University</institution>, Manassas, VA,<country>USA</country></aff><aff id="aff6"><label>6</label><institution>Department of Experimental Medicine and Surgery, University of Rome Tor Vergata</institution>, Rome,<country>Italy</country></aff><aff id="aff7"><label>7</label><institution>Dept of Public Health and Infectious Diseases, Institute Pasteur Cenci Bolognetti Foundation, Sapienza University of Rome</institution>, Rome,<country>Italy</country></aff><aff id="aff8"><label>8</label><institution>San Raffaele Pisana Scientific Institute for Research, Hospitalization and Health Care</institution>, Rome,<country>Italy</country></aff></contrib-group><author-notes><corresp id="caf1"><label>*</label><institution>Istituto Superiore di Sanità</institution>, Viale Regina Elena, 299, Rome 00161, <country>Italy</country>. Tel: +39 0649902305; Fax: +39 0649903561; E-mail: <email>andrea.savarino@iss.it</email></corresp><fn fn-type="present-address" id="note1"><label>9</label><p>These authors contributed equally to this work.</p></fn></author-notes><pub-date pub-type="ppub"><month>12</month><year>2013</year></pub-date><pub-date pub-type="epub"><day>05</day><month>12</month><year>2013</year></pub-date><pub-date pub-type="pmc-release"><day>1</day><month>12</month><year>2013</year></pub-date><volume>4</volume><issue>12</issue><fpage>e944</fpage><lpage></lpage><history><date date-type="received"><day>10</day><month>09</month><year>2013</year></date><date date-type="rev-recd"><day>26</day><month>10</month><year>2013</year></date><date date-type="accepted"><day>31</day><month>10</month><year>2013</year></date></history><permissions><copyright-statement>Copyright © 2013 Macmillan Publishers Limited</copyright-statement><copyright-year>2013</copyright-year><copyright-holder>Macmillan Publishers Limited</copyright-holder><license license-type="open-access" xlink:href="http://creativecommons.org/licenses/by-nc-nd/3.0/"><license-p>This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivs 3.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-nd/3.0/</license-p></license></permissions><abstract><p>Central memory (T<sub>CM</sub>) and transitional memory (T<sub>TM</sub>) CD4<sup>+</sup> T cells are known to be the major cellular reservoirs for HIV, as these cells can harbor a transcriptionally silent form of viral DNA that is not targeted by either the immune system or current antiretroviral drug regimens. In the present study, we explored the molecular bases of the anti-HIV reservoir effects of auranofin (AF), a pro-oxidant gold-based drug and a candidate compound for a cure of AIDS. We here show that T<sub>CM</sub> and T<sub>TM</sub> lymphocytes have lower baseline antioxidant defenses as compared with their naive counterpart. These differences are mirrored by the effects exerted by AF on T-lymphocytes: AF was able to exert a pro-differentiating and pro-apoptotic effect, which was more pronounced in the memory subsets. AF induced an early activation of the p38 mitogen-activated protein kinase (p38 MAPK) followed by mitochondrial depolarization and a final burst in intracellular peroxides. The pro-differentiating effect was characterized by a downregulation of the CD27 marker expression. Interestingly, AF-induced apoptosis was inhibited by pyruvate, a well-known peroxide scavenger, but pyruvate did not inhibit the pro-differentiating effect of AF, indicating that the pro-apoptotic and pro-differentiating effects involve different pathways. In conclusion, our results demonstrate that AF selectively targets the T<sub>CM</sub>/T<sub>TM</sub> lymphocyte subsets, which encompass the HIV reservoir, by affecting redox-sensitive cell death pathways.</p></abstract><kwd-group><kwd>auranofin</kwd><kwd>HIV cure</kwd><kwd>memory compartment</kwd><kwd>apoptosis</kwd><kwd>differentiation effect</kwd><kwd>oxidative stress</kwd></kwd-group></article-meta></front><floats-group><fig id="fig1"><label>Figure 1</label><caption><p>Dot plots showing anti-CD27 and Annexin V staining after 48 h of treatment with AF (gate on live cells) in (<bold>a</bold>) CD4<sup>+</sup> and (<bold>b</bold>) CD8<sup>+</sup> T-cell subpopulations. CD4<sup>+</sup> and CD8<sup>+</sup> T<sub>N</sub>, T<sub>CM</sub>, T<sub>TM</sub> and T<sub>EM</sub> T cells were separated by sorting and treated with AF at 250 n<sc>M</sc> or left untreated (gated on live CD4<sup>+</sup> T cells on the basis of the physical parameters). The dot plots show data from one representative experiment out of five (<bold>a</bold>) and out of three (<bold>b</bold>) with similar results</p></caption><graphic xlink:href="cddis2013473f1"></graphic></fig><fig id="fig2"><label>Figure 2</label><caption><p>Baseline antioxidant levels in sorted CD4<sup>+</sup> T-cell subpopulations reflect their susceptibility to AF. (<bold>a</bold>) Total GSH levels in sorted CD4<sup>+</sup> T-cell subpopulations. CD4<sup>+</sup> T-cell subpopulations were separated by sorting and baseline GSH levels were measured. Data points represent the means from three independent experiments normalized to T<sub>N</sub> cells. Data are shown as median±interquartile range (<italic>n</italic>=3; <italic>P</italic><0.001; repeated measures ANOVA). (<bold>b</bold>) Total thiol content in sorted CD4<sup>+</sup> T-cell subpopulations. The thiol content was measured, in all CD4<sup>+</sup> T-cell subpopulations, by FACS after labeling cells with ThiolTracker violet dye. The data displayed in both the dot plot and the <italic>x</italic>, <italic>y</italic> graph are expressed as the median of fluorescence intensity. On the ‘<italic>x</italic>' axis of the <italic>x</italic>, <italic>y</italic> graph, the level of CD4<sup>+</sup> T-cell differentiation was associated, for clarity purposes, to an increasing score ranging from 0 to 3 (0=T<sub>N</sub>; 1=T<sub>CM</sub>; 2=T<sub>TM</sub>; 3=T<sub>EM</sub>; <italic>P</italic><0.05; Spearman's correlation test). (<bold>c</bold>) Replication of the effects of AF on CD4<sup>+</sup> T cells by the TrxR inhibitor arsenic trioxide (As<sub>2</sub>O<sub>3</sub>). The dot plots show the effect of AF and As<sub>2</sub>O<sub>3</sub> on total CD4<sup>+</sup> T cells after 48 h of treatment, analyzed by CD27 (<italic>y</italic> axis) and Annexin V (<italic>x</italic> axis) staining. The dot plot shows data from one representative experiment out of three with similar results</p></caption><graphic xlink:href="cddis2013473f2"></graphic></fig><fig id="fig3"><label>Figure 3</label><caption><p>Role of p38 MAPK in the pro-differentiating and pro-apoptotic effects of AF. (<bold>a</bold>) Activation of p38 MAPK by AF treatment. CD4<sup>+</sup> T cells were incubated with 250 n<sc>M</sc> AF for 0–48 h. Protein extracts were prepared at the indicated time points and analyzed on western blot probed with specific antibody against the phosphorylated form of p38 MAPK (p-p38; Tyr182). Loading was controlled with an antibody against total p38 MAPK on the according blot. Respective bands were quantified using Quantity One software and relative p38 MAPK activation was calculated and normalized to the loading control. The blot is shown from one representative experiment out of the two performed. Data in densitometric analysis are graphed as means±s.d. of the two experiments performed (donors: <italic>n</italic>=2; *<italic>P</italic><0.05; ***<italic>P</italic><0.001; one-tailed Student's <italic>t</italic>-test). (<bold>b</bold>) Effect of AF and the p38 MAPK inhibitor SB203580 on CD27 and Annexin V staining in human CD4<sup>+</sup> T cells after 48 h of treatment. The dot plot shows data from one representative experiment out of three (similar results). (<bold>c</bold>) Percentages of CD27<sup>−</sup>/Annexin V<sup>+</sup> CD4<sup>+</sup> T cells after 48 h of treatment with AF and SB203580. Data are shown as means±s.d. (n of donors=3; *<italic>P</italic><0.05; **<italic>P</italic> <0.01; ***<italic>P</italic><0.001; Newman–Keuls <italic>post-hoc</italic> test following repeated measures ANOVA and <italic>LOGIT</italic> transformation). (<bold>d</bold>) Percentages of CD27<sup>−</sup>/Annexin V<sup>−</sup> T cells after 48 h of treatment. Data are shown as means±s.d. (n of donors=3; *<italic>P</italic><0.05; **<italic>P</italic> <0.01; ***<italic>P</italic><0.001; Newman–Keuls <italic>post-hoc</italic> test following repeated measures ANOVA and <italic>LOGIT</italic> transformation)</p></caption><graphic xlink:href="cddis2013473f3"></graphic></fig><fig id="fig4"><label>Figure 4</label><caption><p>Analysis of MMP (Δψm) in CD4<sup>+</sup> T cells after AF treatment. Cells were stimulated with AF for 12–48 h and stained with the JC-1 probe. After staining with JC-1, live cells display red fluorescence (high MMP), whereas apoptotic cells display intermediate or green fluorescence (low MMP). Note that the relatively high rates of cells displaying low MMP observed in the controls are in line with a spontaneous trend to undergo apoptosis in the memory compartment of non-stimulated CD4<sup>+</sup> T cells (see <xref ref-type="fig" rid="fig1">Figure 1</xref>). (<bold>a</bold>) Dot plots of red and green fluorescence at 12, 24 and 48 h. (<bold>b</bold>) Histograms showing the decrease in mean red fluorescence intensity induced by auranofin at 48 h. Data are shown as mean±s.d. (<italic>n</italic>=4; *<italic>P</italic><0.05; two-tailed paired Student's <italic>t</italic>-test)</p></caption><graphic xlink:href="cddis2013473f4"></graphic></fig><fig id="fig5"><label>Figure 5</label><caption><p>Protein array after AF treatment shows differential modulation of pathways involved in antioxidant responses and cell survival. (<bold>a</bold>) Antioxidant pathways and cytokines; (<bold>b</bold>) transcription factors and kinases; (<bold>c</bold>) cell death and survival pathways, and other proteins. The table was obtained by comparing the intensity level of proteins from each subpopulation of CD4<sup>+</sup> T cells (T<sub>N</sub>, T<sub>CM</sub>, T<sub>TM</sub> and T<sub>EM</sub>), treated with AF for 6 h or left untreated. Endpoints examined are clustered on the horizontal axis. Within the heat maps, red color represents higher levels of relative expression, black represents same levels and green represents lower levels of relative expression. The proteins are clustered by similarity of their expression profiles</p></caption><graphic xlink:href="cddis2013473f5"></graphic></fig><fig id="fig6"><label>Figure 6</label><caption><p>The role of ROS in AF-induced cell death and differentiation. (<bold>a</bold>) ROS production in CD4<sup>+</sup> T cells. ROS content was measured by flow cytometry after labeling cells with 1,2,3 DHR. The dot plot shows ROS fluorescence in total CD4<sup>+</sup> T cells at different time points. (<bold>b</bold>) Histograms showing median intensity of the DHR fluorescence of CD4<sup>+</sup> T cells from three independent experiments. Data are shown as mean±s.d. (**<italic>P</italic><0.01; Bonferroni's <italic>post-hoc</italic> test following two-way ANOVA). (<bold>c</bold>) Effect of pyruvate, a scavenger of peroxide, on AF-induced cell death and differentiation. Dot plots show CD27 (<italic>y</italic> axis) and Annexin V (<italic>x</italic> axis) staining of human CD4<sup>+</sup> T cells after 48 h of treatment. (<bold>d</bold>) Histogram showing the percentages of CD27<sup>−</sup>/Annexin V<sup>+</sup> T cells after 48 h of treatment from three independent experiments. Data are shown as means±s.d. (*<italic>P</italic><0.05; **<italic>P</italic> <0.01; ***<italic>P</italic><0.001; Newman–Keuls <italic>post-hoc</italic> test following repeated measures ANOVA and <italic>LOGIT</italic> transformation). (<bold>e</bold>) Percentages of CD27<sup>−</sup>/Annexin V<sup>−</sup> T cells after 48 h of treatment from three independent experiments. Data are shown as mean±s.d. (*<italic>P</italic><0.05; **<italic>P</italic><0.01; ***<italic>P</italic><0.001; Newman–Keuls <italic>post-hoc</italic> test following repeated measures ANOVA and <italic>LOGIT</italic> transformation)</p></caption><graphic xlink:href="cddis2013473f6"></graphic></fig><fig id="fig7"><label>Figure 7</label><caption><p>AF-induced phenotype changes in CD4<sup>+</sup> T cells from HIV-infected individuals. Shown are the proportions of CD4<sup>+</sup> T-cell subpopulations of human HIV<sup>+</sup> subjects, under ART, after 2 days of treatment with auranofin. CD4<sup>+</sup> T-naive (T<sub>N</sub>; i.e., CD45RA<sup>+</sup> CD27<sup>+</sup> CCR7<sup>+</sup>), CD4<sup>+</sup> T-central memory (T<sub>CM</sub>; CD45RA<sup>−</sup> CD27<sup>+</sup> CCR7<sup>+</sup>), CD4<sup>+</sup> T-transitional memory (T<sub>TM</sub>; CD45RA<sup>−</sup> CD27<sup>+</sup> CCR7<sup>−</sup>) and CD4<sup>+</sup> T-effector memory (T<sub>EM</sub>; CD45RA<sup>−</sup> CD27<sup>−</sup> CCR7<sup>−</sup>), CCR7<sup>+</sup> CD27<sup>−</sup>. The <italic>P</italic>-values are shown, as obtained by paired <italic>t</italic>-test analysis following a <italic>LOGIT</italic> transformation to restore normality</p></caption><graphic xlink:href="cddis2013473f7"></graphic></fig><fig id="fig8"><label>Figure 8</label><caption><p>(<bold>a</bold> and <bold>b</bold>) Proposed model of the molecular mechanisms underlying AF-induced apoptosis of human primary CD4<sup>+</sup> central and transitional memory T cells</p></caption><graphic xlink:href="cddis2013473f8"></graphic></fig></floats-group></pmc><affiliations><list><country><li>Italie</li><li>États-Unis</li></country></list><tree><country name="Italie"><noRegion><name sortKey="Chirullo, B" sort="Chirullo, B" uniqKey="Chirullo B" first="B" last="Chirullo">B. Chirullo</name></noRegion><name sortKey="Boe, A" sort="Boe, A" uniqKey="Boe A" first="A" last="Boe">A. Boe</name><name sortKey="Garaci, E" sort="Garaci, E" uniqKey="Garaci E" first="E" last="Garaci">E. Garaci</name><name sortKey="Limongi, D" sort="Limongi, D" uniqKey="Limongi D" first="D" last="Limongi">D. Limongi</name><name sortKey="Norelli, S" sort="Norelli, S" uniqKey="Norelli S" first="S" last="Norelli">S. Norelli</name><name sortKey="Palamara, A T" sort="Palamara, A T" uniqKey="Palamara A" first="A T" last="Palamara">A T Palamara</name><name sortKey="Palamara, A T" sort="Palamara, A T" uniqKey="Palamara A" first="A T" last="Palamara">A T Palamara</name><name sortKey="Pelosi, E" sort="Pelosi, E" uniqKey="Pelosi E" first="E" last="Pelosi">E. Pelosi</name><name sortKey="Savarino, A" sort="Savarino, A" uniqKey="Savarino A" first="A" last="Savarino">A. Savarino</name><name sortKey="Sgarbanti, R" sort="Sgarbanti, R" uniqKey="Sgarbanti R" first="R" last="Sgarbanti">R. Sgarbanti</name><name sortKey="Shytaj, I L" sort="Shytaj, I L" uniqKey="Shytaj I" first="I L" last="Shytaj">I L Shytaj</name></country><country name="États-Unis"><noRegion><name sortKey="Alvarez, D" sort="Alvarez, D" uniqKey="Alvarez D" first="D" last="Alvarez">D. Alvarez</name></noRegion><name sortKey="Chomont, N" sort="Chomont, N" uniqKey="Chomont N" first="N" last="Chomont">N. Chomont</name><name sortKey="Dafonseca, S" sort="Dafonseca, S" uniqKey="Dafonseca S" first="S" last="Dafonseca">S. Dafonseca</name><name sortKey="Das, B" sort="Das, B" uniqKey="Das B" first="B" last="Das">B. Das</name><name sortKey="Iii Petricoin, E" sort="Iii Petricoin, E" uniqKey="Iii Petricoin E" first="E" last="Iii Petricoin">E. Iii Petricoin</name><name sortKey="Liotta, L" sort="Liotta, L" uniqKey="Liotta L" first="L" last="Liotta">L. Liotta</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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