Brigitte Autran

Polytech Paris-UPMC, Lutetia Parisorum, Île-de-France, France

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Publications (350)2120.15 Total impact

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    ABSTRACT: Residual immune activation was studied in 51 HIV-infected individuals, 16 with viral load between 1 and 20 copies/ml and 35 with viral load less than 1 copy/ml, and compared with results in 20 healthy blood donors. Higher T-cell activation and IP-10/CXCL10, MIG/CXCL9 and sCD14 plasma levels persisted in both HIV+ groups. The proportion of activated HLA-DR+ CD4 T cells was inversely correlated with the CD4 nadir and the current CD4 cell counts.
    AIDS (London, England) 07/2015; DOI:10.1097/QAD.0000000000000815 · 6.56 Impact Factor
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    ABSTRACT: HIV-1 specific immune responses induced by a dendritic cells (DCs) therapeutic vaccine might have some effect on viral reservoir. We measured total and integrated HIV-1 DNA in isolated CD4 T cells in patients on cART randomized to receive DC pulsed with autologous HIV-1 (n=24) (DC-HIV-1) or with non-pulsed DCs (n=12) (DC-control) at 6 time-points: before any cART, before STOP1 (first cART interruption 56 weeks before the first immunization to isolate virus for pulsing DCs), before and after vaccinations (VAC1 and VAC2) and at weeks 12 and 48 after second cART interruption. Vaccinations did not influence HIV-1 DNA levels in vaccinated subjects. After cART interruption post-vaccination (week 12), while total HIV-1 DNA significantly increased in both arms, integrated HIV-1 DNA did not change in vaccinees (1.8 to 1.9, p=0.22) and increased in controls (1.8 to 2.1, p=0.02) (p=0.03 for the difference between groups). However, this lack of increase of integrated HIV-1 DNA observed in DC-HIV-1 group was transient and at week 48 after cART interruption no differences were observed between groups. HIV-1 specific T cells responses at VAC2 time-point were inversely correlated with total and integrated HIV-1 after cART interruption in vaccinees (r=-0.69, p=0.002 and r=-0.82, p<0.0001, respectively). No correlations were found in controls. HIV-1-specific T-cell immune responses elicited by DC therapeutic vaccines drive changes in HIV-1 DNA after vaccination and cART interruption. There is an intense interest in developing strategies to target HIV-1 reservoirs that create barriers to cure. The development of therapeutic vaccines aimed at enhancing immune mediated clearance of virus producing cells is of high priority. Few therapeutic vaccine clinical trials have investigate the role of therapeutic vaccines as a strategy to safely eliminate or control viral reservoirs. We recently reported that a dendritic cell based therapeutic vaccine was able to decrease significantly viral set-point in vaccinated patients with a concomitant increase in HIV-1--specific T cell responses. HIV-1 specific T cell immune responses elicited by this therapeutic dendritic cell vaccine drove changes of viral reservoir after vaccinations and significantly delayed the replenishment of integrated HIV-1 DNA after cART interruption. These data help to understand how an immunization could shift the virus/host balance and are instrumental to better design strategies to reach the functional cure of HIV-1 infection. Copyright © 2015, American Society for Microbiology. All Rights Reserved.
    Journal of Virology 06/2015; DOI:10.1128/JVI.01062-15 · 4.65 Impact Factor
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    ABSTRACT: The aim of the study was to assess the impact of rapid and sustained viral control produced by combination antiretroviral therapy (cART) on HIV-associated immune activation and inflammation. In this longitudinal observational study, we examined changes in interleukin-6 (IL-6), interferon-γ-inducible protein-10 (IP-10), monokine induced by interferon-γ (MIG) and soluble CD14 (sCD14) levels during 2 years of effective first-line cART. Biomarker levels before and after cART were compared with those observed in healthy subjects, using the Wilcoxon signed rank test. Elevated biomarker levels were defined with respect to values for healthy subject (mean + 2 standard deviations). Factors associated with persistently elevated biomarker levels after 2 years of cART were identified by logistic regression. We included in the study 139 patients with a median HIV-1 RNA level of 4.8 log10 HIV-1 RNA copies/mL and a median CD4 cell count of 294 cells/μL at cART initiation [day 0 (D0)]. At D0, all biomarker levels were higher than in healthy subjects (P < 0.05). After 2 years of cART, IL-6, IP-10 and MIG levels fell significantly, by a median of 0.54, 420 and 1107 pg/mL, respectively (all P < 0.001), and were no longer elevated in > 75% of patients. In contrast, sCD14 levels did not change significantly (0.18 × 10(6) pg/mL; P = 0.102) and remained elevated. Older age was associated with elevated levels of IP-10 [odds ratio (OR) 1.60 per 10 years older; P = 0.047] and MIG (OR 1.92 per 10 years older; P = 0.007) after 2 years of cART. The rapid and sustained viral suppression produced by first-line cART reduced IL-6, IP-10 and MIG to normal levels, while sCD14, a marker of monocyte activation, remained elevated. High levels of IP-10 and MIG tended to persist in older patients. © 2015 British HIV Association.
    HIV Medicine 05/2015; DOI:10.1111/hiv.12257 · 3.45 Impact Factor
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    ABSTRACT: Therapeutic control of HIV replication reduces the size of the viral reservoir, particularly among central memory CD4+ T cells, and this effect might be accentuated by early treatment. We examined the effect of ART initiated at the time of the primary HIV infection (early ART), lasting 2 and 6 years in 11 and 10 patients, respectively, on the HIV reservoir in peripheral resting CD4+ T cells, sorted into naive (TN), central memory (TCM), transitional memory (TTM) and effector memory (TEM) cells, by comparison with 11 post-treatment controllers (PTCs). Between baseline and 2 years, CD4+ T cell subset numbers increased markedly (P < 0.004) and HIV DNA levels decreased in all subsets (P < 0.009). TTM cells represented the majority of reservoir cells at both timepoints, T cell activation status normalized and viral diversity remained stable over time. The HIV reservoir was smaller after 6 years of early ART than after 2 years (P < 0.019), and did not differ between PTCs and patients treated for 6 years. One patient, who had low reservoir levels in all T cell subsets after 2 years of treatment similar to the levels in PTCs, spontaneously controlled viral replication during 18 months off treatment. Early prolonged ART thus limits the size of the HIV reservoir, protects long-lived cells from persistent infection and may enhance post-treatment control. © The Author 2015. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.
    Journal of Antimicrobial Chemotherapy 04/2015; DOI:10.1093/jac/dkv084 · 5.44 Impact Factor
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    ABSTRACT: Immunovirological consequences of a switch to a maraviroc/raltegravir dual therapy were analyzed in 16 HIV-infected patients with persistent viral load below 50 copies/ml. At 26-week postswitch, the CD4/CD8 ratio decreased and the CD8 T-cell activation increased. A decrease in classical monocytes was associated with a shift toward a proinflammatory monocyte profile and negatively correlated with ultrasensitive viral load. Thus, this therapeutic switch induced a proinflammatory profile probably driven by a slight loss of virus control.
    AIDS (London, England) 02/2015; 29(7). DOI:10.1097/QAD.0000000000000626 · 6.56 Impact Factor
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    ABSTRACT: HBV infection is a major cause of liver cirrhosis and hepatocellular carcinoma. Although HBV infection can be efficiently prevented by vaccination, and treatments are available, to date there is no reliable cure for the >240 million individuals that are chronically infected worldwide. Current treatments can only achieve viral suppression, and lifelong therapy is needed in the majority of infected persons. In the framework of the French National Agency for Research on AIDS and Viral Hepatitis 'HBV Cure' programme, a scientific workshop was held in Paris in June 2014 to define the state-of-the-art and unanswered questions regarding HBV pathobiology, and to develop a concerted strategy towards an HBV cure. This review summarises our current understanding of HBV host-interactions leading to viral persistence, as well as the roadblocks to be overcome to ultimately address unmet medical needs in the treatment of chronic HBV infection. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.
    Gut 02/2015; 64(8). DOI:10.1136/gutjnl-2014-308943 · 13.32 Impact Factor
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    ABSTRACT: Achievement of a cure for HIV infection might need reactivation of latent virus and improvement of HIV-specific immunity. As an initial step, in this trial we assessed the effect of antiretroviral therapy intensification and immune modulation with a DNA prime and recombinant adenovirus 5 (rAd5) boost vaccine.
    The Lancet HIV 02/2015; 2(3). DOI:10.1016/S2352-3018(15)00026-0
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    ABSTRACT: Increased risk of cardiovascular disease in patients infected with HIV has been attributed to immune activation, inflammation, and immunosenescence, all of which are linked to chronic immune activation by viral infections, particularly cytomegalovirus (CMV). Our aim is to evaluate the impact of these atherogenic markers in HIV-infected patients who never smoked. Exposure-matched, cross-sectional study. In 59 HIV-infected individuals [n = 30 undergoing ≥4 years of antiretroviral therapy (ART); n = 29 never treated with ART] and 30 age-matched HIV-negative controls, we measured the level of activation and senescence, as well as the frequency of CMV-specific T cells, on peripheral blood mononuclear cells, while examining their association with carotid intima-media thickness. Partial correlations were adjusted for age, systolic blood pressure, and nadir CD4 cell count. The previously described roles of T-cell activation, CMV, and immunosenescence in the atherosclerotic risk of HIV-infected patients, as assessed by carotid intima-media thickness, were not apparent in our cohort of particularly 'healthy' HIV-infected never-smokers. In HIV-infected individuals at low cardiovascular disease risk, our data show that the increased risk of carotid atherosclerosis is not associated with immunological markers described to be associated with HIV disease progression.
    AIDS (London, England) 01/2015; 29(3):287-93. DOI:10.1097/QAD.0000000000000539 · 6.56 Impact Factor
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    ABSTRACT: Background Despite control of HIV infection under antiretroviral therapy (ART), immune T-cell activation persists in patients with controlled HIV infection, who are at higher risk of inflammatory diseases than the general population. PMNs play a key role in host defenses against invading microorganisms but also potentiate inflammatory reactions in cases of excessive or misdirected responses. Objective The aim of our study was to analyze PMN functions in 60 ART-treated and controlled HIV-infected patients (viral load, <20 RNA copies/mL; CD4 count, ≥350 cells/mm3) with (HIV[I] group) and without (HIV[NI] group) diseases related to an inflammatory process and to compare them with 22 healthy control subjects. Methods Flow cytometry was used to evaluate PMN functions in whole-blood conditions. We studied in parallel the activation markers of T lymphocytes and monocytes and the proinflammatory cytokine environment. Results Blood samples from HIV-infected patients revealed basal PMN hyperactivation associated with deregulation of the apoptosis/necrosis equilibrium. Interestingly, this hyperactivation was greater in HIV(I) than HIV(NI) patients and contrasted with a lack of monocyte activation in both groups. The percentage of circulating cells producing IL-17 was also significantly higher in HIV-infected patients than in control subjects and was positively correlated with markers of basal PMN activation. In addition, the detection of IL-22 overproduction in HIV(NI) patients suggests that it might contribute to counteracting chronic inflammatory processes during HIV infection. Conclusions This study thus demonstrates the presence of highly activated PMNs in HIV-infected patients receiving effective ART and the association of these cells with a specific IL-17/IL-22 environment.
    Journal of Allergy and Clinical Immunology 07/2014; 134(5). DOI:10.1016/j.jaci.2014.05.040 · 11.25 Impact Factor
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    ABSTRACT: Cytomegalovirus (CMV) remains a leading cause of morbidity after solid organ transplantation. The efficiency of antivirals for the treatment of CMV infections may be hampered because of the emergence of CMV resistance to antivirals. The development of CMV multidrug-resistance, that remains uncommon but does occur, constitutes a clinically challenging complication and may contribute to difficult therapeutic management and adverse clinical outcome. We report here the observation of the emergence of a multidrug-resistant CMV infection in a heart-transplant recipient, and review the literature on similar cases to identify the potential strategies for the successful management of CMV multidrug-resistance among immunocompromised patients.
    Antiviral therapy 06/2014; 20(2). DOI:10.3851/IMP2818 · 3.14 Impact Factor
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    ABSTRACT: The magnitude, quality, and maintenance of immunological memory after infection or vaccination must be considered for future design of effective influenza vaccines. In 2009, the influenza pandemic produced disease that ranged from mild to severe, even fatal, illness in infected healthy adults and led to vaccination of a portion of the population with the adjuvanted, inactivated influenza A(H1N1)pdm09 vaccine. Here, we have proposed a multiparameter quantitative and qualitative approach to comparing adaptive immune memory to influenza 1 year after mild or severe infection or vaccination. One year after antigen encounter, severely ill subjects maintained high levels of humoral and polyfunctional effector/memory CD4+ T cells responses, while mildly ill and vaccinated subjects retained strong cellular immunity, as indicated by high levels of mucosal homing and degranulation markers on IFN-γ+ antigen-specific T cells. A principal component analysis distinguished 3 distinct clusters of individuals. The first group comprised vaccinated and mildly ill subjects, while clusters 2 and 3 included mainly infected individuals. Each cluster had immune memory profiles that differed in magnitude and quality. These data provide evidence that there are substantial similarities between the antiinfluenza response that mildly ill and vaccinated individuals develop and that this immune memory signature is different from that seen in severely ill individuals.
    Journal of Clinical Investigation 06/2014; 124(7). DOI:10.1172/JCI74565 · 13.77 Impact Factor
  • Brigitte Autran · Chiraz Hamimi · Christine Katlama
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    ABSTRACT: In the global fight against HIV/AIDS, the persistence of viral reservoirs, established early during primary infection by the Human Immunodeficiency virus (HIV), is probably the biggest challenge to finding a cure for HIV, despite the major progress provided by antiviral treatments. This persistence reflects virus latency in the immune system and imposes the prospect of life-long treatment with risk of toxicities, and major costs for society. Innovative strategies aimed at purging these viral reservoirs are therefore required, but the complexity of the latency mechanisms has made a sterilization cure difficult to realize until now. However, recent cases of HIV remission have encouraged the research community, and a functional cure seems to be a more realistic goal to attempt. A better understanding of the mechanisms responsible for such latency has been provided by basic research, although recent attempts at purging the reservoirs by disrupting latency have been somewhat disappointing. In contrast, the early initiation of anti-retroviral treatment appears to be extremely beneficial for HIV remission, as recently suggested by the Mississippi baby case or by the series of post-treatment controllers, respectively. Early treatment initiation can indeed rapidly limit the size of viral reservoirs, or hamper their formation and preserve the host’s immune responses. Despite these encouraging results, it is nevertheless important to deploy more effort toward a better understanding of latency mechanisms and to the development of innovative approaches and molecules in the hope of achieving a cure for HIV.
    06/2014; 6(2):171-182. DOI:10.1007/s40506-014-0017-1
  • La Revue de Médecine Interne 06/2014; 35:A44. DOI:10.1016/j.revmed.2014.03.038 · 1.32 Impact Factor
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    ABSTRACT: Introduction – objectifs Exploration du réservoir dans les sous-populations CD4 circulantes (SP) après 2 ans d’un traitement antirétroviral initié en primoinfection VIH (PHI2). Matériels et méthodes 12 patients randomisés de l’essai OPTIPRIM. J0 et M24 : quantification de l’ADN-VIH total et analyse phylogénétique de la quasiespèce virale dans les cellules triées quiescentes, naïves (TN), mémoires centrales (TCM), transitionnelles (TTM), effectrices (TEM). M24 : capacité des SP à produire des virus par activation in vitro et comparaison des niveaux d’ADN-VIH dans les SP des PHI2 versus 9 patients traités en PHI 6 ans en médiane (PHI6) et 11 contrôleurs post-traitement traités en PHI (PTC). Résultats De J0 à M24 : augmentation du nombre des SP (p < 0,004), diminution du niveau d’ADN-VIH médian dans les PBMC de – 1,43 (p = 0,001), – 0,74 (TN), – 1,45 (TCM), – 1,48 (TTM), – 1,34 (TEM) (p < 0,004). Pas d’évolution de la diversité virale et production virale induite dans toutes les SP. Les TN et TCM étaient moins infectées que TTM et TEM (p < 0,009) et contribuaient moins au réservoir que les TTM (p = 0,019). Les niveaux d’ADN-VIH dans les SP des PHI2 étaient plus élevés que les faibles et similaires niveaux chez les PHI6 et PTC (p < 0,019). Un PHI2 maintien un statut de PTC 18 mois après arrêt du traitement avec des niveaux de réservoir, similaires à ceux des PTC. Conclusion Un traitement précoce de deux ans en PHI protège les TCM et TN de l’infection. Un traitement de plus longue durée est nécessaire pour atteindre une réduction profonde du réservoir VIH et augmenter les cas de PTC.
    Médecine et Maladies Infectieuses 06/2014; 44(6):9–10. DOI:10.1016/S0399-077X(14)70061-7 · 0.91 Impact Factor
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    ABSTRACT: The aim of the study was to determine the molecular mechanisms underlying the quasi-equilibrium between HIV and its host in the model of functional cure represented by elite controllers who spontaneously maintain exceptionally low levels of HIV reservoirs. Whole-genome transcriptional study and quantification of the cell-associated HIV DNA and HIV RNA levels of the four major resting CD4 T-cell subsets in HIV-1-infected elite controllers, viremic long-term nonprogressors (vir-LTNPs), and uninfected individuals. We compared the whole-genome transcriptional profiles (ArrayExpress accession number E-MTAB-1480) of the four major resting CD4 T-cell subsets [naive (TN), central-memory (TCM), transitional-memory (TTM), and effector-memory (TEM)] from 14 HIV-1-infected individuals including seven elite controllers (E-LTNPs) and seven vir-LTNPs, and from seven uninfected individuals. The HIV-1 cellular DNA and mRNA levels were quantified in parallel in each sorted subset. Host gene transcriptomes followed subset differentiation and viremia except in E-LTNPs wherein TCM, the main CD4 cell compartment, showed the highest activity with three specific signatures involving overexpression of TCR and costimulation signaling pathways, overexpression of the PRDM-1/Blimp-1 transcriptional repressor, and downmodulation of type-I IFN-related genes. Among subsets, the PRDM1/Blimp-1 upregulation was associated with lower levels of both cellular HIV-DNA and HIV mRNA levels. This unique Blimp-1 transcriptional repressor signature and the contrast between host and virus transcriptional activities in TCM from elite controllers suggest Blimp-1 might be involved in controlling the HIV reservoirs in the key TCM subset.
    AIDS (London, England) 05/2014; 28(11). DOI:10.1097/QAD.0000000000000295 · 6.56 Impact Factor
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    ABSTRACT: Rationale: The biology of fatal pandemic influenza infection remains undefined. Methods: This multicenter study included 34 unvaccinated patients with very severe or fatal confirmed influenza A(H1N1) infections. It analyzed plasma A(H1N1) 2009 RT-PCR, hemagglutinin 222G viral mutation, and humoral and cellular immune responses to the virus, assessed in hemagglutination inhibition (HI), microneutralization, ELISA, lymphoproliferative, ELISpot IFN-, and cytokine/chemokine assays. Measurements and Main Results: The patients' median age was 34 years. Influenza A(H1N1) 2009 viremia was detected in 4/34 cases, and a 222G hemagglutinin mutation in 7/17 cases, all of them with SOFA≥8. HI antibodies were detectable in 19/26 survivors and undetectable in all 6 fatal fulminant cases. ELISA and microneutralization titers were concordant. B-cell immunophenotyping and plasma levels of immunoglobulin classes did not differ between patients who survived and died. After immune complex dissociation, influenza ELISA serology became strongly positive in the bronchoalveolar lavage of the 2 fatal cases tested. H1N1-specific T-cell responses in lymphoproliferative and IFN- assays were weak in survivors' peripheral blood, and lymphoproliferative assays were negative in the 3 fatal cases tested. Plasma levels of IL-6 and IL-10 were high in fatal cases and correlated with severity. Finally, a negative HI serology 4 days after the onset of influenza symptoms predicted death from fulminant influenza (p=0.04). Conclusions: Early negative A(H1N1) 2009 HI serology can predict death from influenza. This negative serology in fatal cases in young adults reflects the trapping of anti-H1N1 antibodies in immune complexes in the lungs, associated with poor specific helper T-cell response.
    American Journal of Respiratory and Critical Care Medicine 03/2014; 189(10). DOI:10.1164/rccm.201311-2071OC · 11.99 Impact Factor
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    ABSTRACT: Few studies have compared the impact of different antiretroviral regimens on residual immune activation and inflammation with discordant results. Aim of the study was to investigate the impact of various antiretroviral regimens on markers of immune activation and inflammation during the first two years of effective therapy. We studied HIV-infected antiretroviral-naive patients who began cART with either abacavir/lamivudine or tenofovir/emtricitabine, combined with ritonavir-boosted lopinavir (LPV/r), atazanavir (ATV/r) or efavirenz (EFV). All the patients had a virological response within 6 months, which was maintained for 2 years with no change in their ART regimen. C-reactive protein (hs-CRP), interleukin-6 (IL-6), soluble CD14 (sCD14), monokine induced by interferon-gamma (MIG) and interferon-gamma-inducible protein-10 (IP-10) were measured in stored plasma obtained at cART initiation and 24 months later. Mean changes from baseline were analyzed on loge-transformed values and multivariable linear regression models were used to study the effect of the treatment components, after adjusting for factors that might have influenced the choice of ART regimen or biomarker levels. Differences were expressed as the mean fold change percentage difference (Delta). Seventy-eight patients (91% males) with a median age of 43 years met the inclusion criteria. Their median baseline CD4 cell count was 315/mm3 and HIV-1 RNA level 4.6 log10 copies/ml. During the 2-years study period, IL-6, IP-10 and MIG levels fell significantly, while hs-CRP and sCD14 levels remained stable. IP-10 and MIG levels declined significantly less strongly with ATV/r than with EFV (IP-10Delta -57%, p = 0.011; MIGDelta -136%, p = 0.007), while no difference was noted between LPV/r and EFV. The decline in IL-6 did not differ significantly across the different treatment components. After the first 2 years of successful cART, IL-6, IP-10 and MIG fell markedly while hs-CRP and sCD14 levels remained stable. The only impact of ART regimen was a smaller fall in markers of immune activation with ATV/r than with EFV. Our results suggest that these markers could be worthwhile when evaluating new antiretroviral drugs.
    BMC Infectious Diseases 03/2014; 14(1):122. DOI:10.1186/1471-2334-14-122 · 2.61 Impact Factor
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    ABSTRACT: Idiopathic CD4 T lymphocytopenia (ICL) is a rare and severe condition with limited available data. We conducted a French multicenter study to analyze the clinical and immunologic characteristics of a cohort of patients with ICL according to the Centers for Disease Control criteria.We recruited 40 patients (24 female) of mean age 44.2 ± 12.2 (19-70) years. Patients underwent T-lymphocyte phenotyping and lymphoproliferation assay at diagnosis, and experiments related to thymic function and interferon (IFN)-γ release by natural killer (NK) cell were performed. Mean follow-up was 6.9 ± 6.7 (0.14-24.3) years. Infectious, autoimmune, and neoplastic events were recorded, as were outcomes of interleukin 2 therapy.In all, 25 patients had opportunistic infections (12 with human papillomavirus infection), 14 had autoimmune symptoms, 5 had malignancies, and 8 had mild or no symptoms. At the time of diagnosis, the mean cell counts were as follows: mean CD4 cell count: 127/mm (range, 4-294); mean CD8: 236/mm (range, 1-1293); mean CD19: 113/mm (range, 3-547); and mean NK cell count: 122/mm (range, 5-416). Most patients had deficiency in CD8, CD19, and/or NK cells. Cytotoxic function of NK cells was normal, and patients with infections had a significantly lower NK cell count than those without (p = 0.01). Patients with autoimmune manifestations had increased CD8 T-cell count. Proliferation of thymic precursors, as assessed by T-cell rearrangement excision circles, was increased. Six patients died (15%). CD4 T-cell count <150/mm and NK cell count <100/mm were predictors of death.In conclusion, ICL is a heterogeneous disorder often associated with deficiencies in CD8, CD19, and/or NK cells. Long-term prognosis may be related to initial CD4 and NK cell deficiency.
    Medicine 03/2014; 93(2):61-72. DOI:10.1097/MD.0000000000000017 · 4.87 Impact Factor
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    ABSTRACT: Although it is established that CD8 T-cell immunity is critical for the control of HIV replication in vivo, the key factors that determine antiviral efficacy are yet to be fully elucidated. Antigen-sensitivity and T-cell receptor (TCR) avidity have been identified as potential determinants of CD8 T-cell efficacy. However, there is no general consensus in this regard because the relationship between these parameters and the control of HIV infection has been established primarily in the context of immunodominant CD8 T-cell responses against the Gag263-272 KK10 epitope restricted by HLA-B27. To investigate the relationship between antigen-sensitivity, TCR avidity and HIV-suppressive capacity in vitro across epitope specificities and HLA class I restriction elements, we used a variety of techniques to study CD8 T-cell clones specific for Nef73-82 QK10 and Gag20-29 RY10, both restricted by HLA-A3, alongside CD8 T-cell clones specific for Gag263-272 KK10. For each targeted epitope, the linked parameters of antigen-sensitivity and TCR avidity correlated directly with antiviral efficacy. However, marked differences in HIV-suppressive capacity were observed between epitope specificities, HLA class I restriction elements and viral isolates. Collectively, these data emphasize the central role of the TCR as a determinant of CD8 T-cell efficacy and demonstrate that the complexities of antigen recognition across epitope and HLA class I boundaries can confound simple relationships between TCR engagement and HIV suppression.
    AIDS (London, England) 12/2013; 28(4). DOI:10.1097/QAD.0000000000000175 · 6.56 Impact Factor
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    ABSTRACT: To characterize the immunity developed by patients infected by chikungunya virus (CHIKV), we studied the intensity and specificity of CHIKV-specific T cells mediated responses in chronic and recovered patients at 12 to 24 months post-infection. T cells were challenged in vitro against CHIKV synthetic peptides covering the length of three viral proteins, capsid, E2 and nsP1 proteins as well as all inactivated virus particles. Cytokine production was assessed by ELISPOT and intracellular labeling. T cells producing IFN-γ were detected against CHIKV in 85% patient's cells either by direct ELISPOT assay (69% of patients) or after expansion of memory T cells allowing the detection of both CD4 and CD8 specific-T cells in 16% additional cases. The IFN-γ response was mainly engaged in response to nsP1 or E2 (52% and 46% cases, respectively) but in only 27% cases against the capsid. The anti-E2 response represented half the magnitude of the total CHIKV IFN-γ production and was mainly directed against the C-terminal half part of the protein. Almost all patients had conserved a T cell specific response against CHIKV with a clear hierarchy of T cell responses (CD8 > CD4) engaged against E2 > nsP1 > capsid. More importantly, the intensity of responses was not significantly different between recovered and chronic patients. These findings constitute key elements to a better understanding of patient T cell immunoreactivity against CHIKV and argue against a possible defect of T cell immunoresponse in the chronicity post-CHIKV infection.
    PLoS ONE 12/2013; 8(12):e84695. DOI:10.1371/journal.pone.0084695 · 3.23 Impact Factor

Publication Stats

12k Citations
2,120.15 Total Impact Points

Institutions

  • 2009–2015
    • Polytech Paris-UPMC
      Lutetia Parisorum, Île-de-France, France
  • 2004–2015
    • Pierre and Marie Curie University - Paris 6
      • Unité immunité et infection
      Lutetia Parisorum, Île-de-France, France
  • 2003–2014
    • Unité Inserm U1077
      Caen, Lower Normandy, France
  • 1987–2014
    • Hôpital La Pitié Salpêtrière (Groupe Hospitalier "La Pitié Salpêtrière - Charles Foix")
      • Service de Médecine Interne 1
      Lutetia Parisorum, Île-de-France, France
  • 2003–2013
    • French Institute of Health and Medical Research
      • Unit of Immunity and Infection
      Lutetia Parisorum, Île-de-France, France
  • 2008–2011
    • Assistance Publique – Hôpitaux de Paris
      • Département de Médecine Interne
      Lutetia Parisorum, Île-de-France, France
    • University of Tours
      Tours, Centre, France
    • Université Paris-Sud 11
      Orsay, Île-de-France, France
  • 2010
    • Centre Hospitalier Gabriel Martin
      Lutetia Parisorum, Île-de-France, France
  • 2003–2007
    • Hôpitaux Universitaires La Pitié salpêtrière - Charles Foix
      Lutetia Parisorum, Île-de-France, France
  • 2001
    • Case Western Reserve University School of Medicine
      • Department of Pathology
      Cleveland, Ohio, United States
  • 1997–2001
    • French National Centre for Scientific Research
      Lutetia Parisorum, Île-de-France, France
    • Hôpital Foch
      Lutetia Parisorum, Île-de-France, France
  • 1994–1996
    • Institut Pasteur de Lille
      Lille, Nord-Pas-de-Calais, France
  • 1987–1991
    • Institut Pasteur
      Lutetia Parisorum, Île-de-France, France
  • 1990
    • University of Pécs
      • Institute of Medical Microbiology and Immunology
      Fuenfkirchen, Baranya, Hungary