Éditeur(s) : HAL CCSD
Résumé : National audience
Congrès de la SPTC - Société de Pharmaco-Toxicologie Cellulaire
Paris, France

hal-01122677
https://hal.archives-ouvertes.fr/hal-01122677

Éditeur(s) : HAL CCSD Lippincott, Williams & Wilkins
Résumé : International audience
OBJECTIVES: The ANRS-112 INTERPRIM trial assessed whether fixed-cycles of antiretroviral treatment interruption (ART-STI) combined or not with pegylated interferon alpha-2b (peg-IFN) could lower viral load and achieve a healthier immune system in patients diagnosed during primary HIV-1-infection (PHI). DESIGN AND METHODS: Patients were randomized to receive either continuous ART (cART) during 72 weeks, or cART during 36 weeks followed by three ART-STIs, or the same ART-STIs associated with peg-IFN during the first 14 weeks and each interruption (ART-STI-IFN). Treatment was stopped at week 72. Final evaluation was based on plasma HIV-RNA level 6 months after the last treatment interruption. RESULTS: Eighty-seven percent of patients achieved undetectable HIV-RNA at week 32, with no deleterious impact of sequential treatment interruptions (STIs). Viral rebounds during interruptions were lower in the ART-STI-IFN than in the ART-STI group and during the second and third interruptions compared with the first one. However, HIV-RNA levels, CD4 T-cell counts and CD4 T/CD8 T ratios were similar between groups after the 6-month interruption, with a persistent effect on CD4 T cells and total cell-associated HIV-DNA levels. Predictive factors of virological outcome were HIV-RNA and HIV-DNA levels at PHI and HIV-DNA levels at treatment interruption. HIV-specific responses did not differ between strategies and were not associated with outcome. Forty-eight percent of patients experienced treatment resumption during long-term follow-up without difference between groups. CONCLUSION: When initiated during PHI, STIs associated or not with IFN did not result in a different outcome as compared to cART. All regimens showed a high response rate and a sustained immunological benefit after cessation.
ISSN: 0269-9370

hal-00875175
https://hal.archives-ouvertes.fr/hal-00875175
DOI : 10.1097/QAD.0b013e32835844d9
PUBMED : 22842994

Éditeur(s) : HAL CCSD Oxford University Press (OUP)
Résumé : International audience
OBJECTIVES: To compare virological effectiveness in patients who continued on a virologically successful first-line boosted protease inhibitor (PI)-containing combination antiretroviral therapy (cART) regimen or who switched to a PI-free cART including efavirenz, nevirapine or abacavir. METHODS: From the French Hospital Database on HIV, we selected 439 patients with undetectable viral load (VL) on a first-line boosted PI-containing cART regimen who switched to a PI-free combination including efavirenz, nevirapine or abacavir. Each of these patients was matched with three patients who continued to take their first-line cART regimen, on the basis of gender, age, CD4 cell count, VL, date of cART initiation and the duration of VL undetectability. Time to virological failure (VF) was analysed with Kaplan-Meier curves and Cox models. RESULTS: The 12 month probabilities of VF were 3.7% and 5.7% in non-switch and switch patients, respectively, and 3.9%, 7.2% and 9.0% in patients switching to efavirenz-, nevirapine- and abacavir-containing cART, respectively. After adjustment, only patients switching to abacavir-containing cART had a higher risk of VF than non-switch patients (adjusted hazard ratio, 1.99; 95% confidence interval, 1.05-3.79). CONCLUSIONS: Switching from a virologically successful first-line boosted PI-containing cART regimen to a non-nucleoside reverse transcriptase inhibitor-containing cART regimen containing either efavirenz or nevirapine is virologically safe, while switching to abacavir-containing cART should be avoided.
ISSN: 0305-7453

hal-00875284
https://hal.archives-ouvertes.fr/hal-00875284
DOI : 10.1093/jac/dkr208
PUBMED : 21636583

Éditeur(s) : HAL CCSD Elsevier
Résumé : International audience
The transcription factor nuclear factor-erythroid 2-related-2 (Nrf2) controls cellular redox homeostasis and displays immunomodulatory properties. Nrf2 alters cytokine expression in murine T cells, but its effects in human T lymphocytes are unknown. This study investigated the expression and activity of Nrf2 in human activated CD4(+) T helper lymphocytes (Th cells) that mediate the adaptive immune response. Th cells were isolated from peripheral blood mononuclear cells and activated with antibodies against CD3 and CD28, mimicking physiologic Th cell stimulation by dendritic cells. Nrf2 is hardly detectable in unstimulated Th cells. Activation of Th cells rapidly and strongly increases the levels of Nrf2 protein by increasing NRF2 gene transcription. Th cell activation also enhances mRNA and protein levels of Nrf2 target genes encoding antioxidant enzymes. Blocking Nrf2 expression using chemical inhibitors or siRNAs prevents these gene inductions. Pretreatment with inorganic arsenic, a Nrf2 inducer that does not alter NRF2 gene expression, increases protein level and transcriptional activity of Nrf2 induced by Th cell stimulation. Inorganic arsenic enhances nuclear translocation of Nrf2, its interaction with the coactivator protein p300, and its DNA binding activity. Inhibition of Nrf2 expression abrogates the effects of inorganic arsenic on mRNA levels of antioxidant genes, but does not alter the expression of IL-2, TNF-α, interferon-γ, or IL-17 in Th cells activated in the absence or presence of the metalloid. In conclusion, this study demonstrates for the first time that stimulation of human Th cells increases transcription of the NRF2 gene and activity of the Nrf2 protein. However, modulation of Nrf2 levels does not modify the secretion of inflammatory cytokines from these T lymphocytes.
ISSN: 0891-5849

hal-01018643
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01018643
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01018643/document
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01018643/file/Nrf2_expression_and_activity_in_human_T_lymphocytes_accepted.pdf
DOI : 10.1016/j.freeradbiomed.2014.03.006

Éditeur(s) : HAL CCSD Elsevier
Résumé : International audience
ISSN: 0891-5849

hal-01117679
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01117679
DOI : 10.1016/j.freeradbiomed.2015.02.003
PUBMED : 25680285

Éditeur(s) : HAL CCSD Wiley
Résumé : International audience
Drug hypersensitivity is known to rely on a drug-specific T-cell response. Amplitude of antigen-specific T-cell response is partly controlled by the size of the antigen-specific naïve CD4(+) T-cell repertoire, but estimate of this repertoire has never been investigated for allergenic drugs. The purpose of this study was to evaluate the frequency of benzylpenicillin-specific CD4(+) T lymphocytes in healthy donors. Co-cultures were established with CD4(+) T lymphocytes from healthy donors and mature autologous dendritic cells loaded with benzylpenicillin coupled to human serum albumin. CD4(+) T lymphocytes were stimulated once a week for 4 weeks with benzylpenicillin coupled to human serum albumin. The CD4(+) T-cell response was measured using an interferon-γ ELISPOT assay. Frequency of benzylpenicillin-specific naive CD4(+) T lymphocytes was then calculated using the Poisson distribution law. Results showed the presence of benzylpenicillin-specific CD4(+) T lymphocytes in 9 of 10 tested healthy donors irrespective of their HLA typing, with a mean frequency of 0.29 cells per million of CD4(+) T cells. Experiments performed on naive (CD45RA(+) ) and on memory (CD45RO(+) ) CD4(+) T lymphocytes showed that these benzylpenicillin-specific CD4(+) T lymphocytes belonged to the naive T-cell subpopulation. This study showed for the first time the existence of naive CD4(+) T lymphocytes specific to benzylpenicillin in healthy donors.
ISSN: 0105-4538

hal-01122172
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01122172
PUBMED : 23751122
DOI : 10.1111/all.12173