Brigitte Autran

Publications of Brigitte Autran

• Immune Responses Driven by Protective Human Leukocyte Antigen Alleles From Long-term Nonprogressors Are Associated With Low HIV Reservoir in Central Memory CD4 T Cells.

  Authors: Benjamin Descours, Veronique Avettand-Fenoel, Catherine Blanc, Assia Samri, Adeline Mélard, Virginie Supervie, Ioannis Theodorou, Guislaine Carcelain, Christine Rouzioux, Brigitte Autran

  Clinical infectious diseases : an official publication of the Infectious Diseases Society of America. 03/2012;

  Background. The stable immune control of human immunodeficiency virus (HIV) in long-term nonprogressors (LTNPs) with protective human leukocyte antigen (HLA) alleles raises the question of whetherBackground. The stable immune control of human immunodeficiency virus (HIV) in long-term nonprogressors (LTNPs) with protective human leukocyte antigen (HLA) alleles raises the question of whether and how these alleles influence the immune distribution of the HIV reservoirs.Methods. Cell-associated HIV-DNA levels were quantified in blood sorted resting CD4 T-cell subsets from 8 LTNPs with and 10 without HLA-B*27 or HLA-B*57 alleles (HLA-B27/B57).Results. A remarkably lower infection level of central memory CD4 T cells (T(CM)) was an exclusive feature that distinguished the HLA-B27/B57 HIV reservoirs from the other ones. In LTNPs, T(CM) protection was correlated with preservation of T(CM) counts, which correlated positively with the magnitude of HIV Gag-specific CD8 T cells. In HLA-B27/B57 LTNPs, a lower activation level of their memory CD4 T cells was associated with lower amounts of cell HIV-DNA in each resting memory CD4 subset and were also associated with higher ratios of HIV Gag-specific CD8 T cells per infected resting CD4 T cell (effector/target [E/T]). As a result, HLA-B27/B57 E/T ratios were negatively correlated with the contribution of memory CD4 T-cell subsets to the total HIV reservoirs.Conclusions. The potent antiviral immunity governed by the protective HLA-B27/B57 alleles, by limiting T(CM) infection and pool exhaustion, are associated with a reduced T(CM) contribution to the HIV reservoir.

• Lack of TGF-β production by hepatitis C virus-specific T cells during HCV acute phase is associated with HCV clearance in HIV coinfection.

  Authors: Sawsan Harfouch, Marguerite Guiguet, Marc-Antoine Valantin, Assia Samri, Zineb Ouazene, Laurence Slama, Stéphanie Dominguez, Anne Simon, Ioannis Theodorou, Vincent Thibault, Brigitte Autran

  Journal of hepatology. 02/2012;

  BACKGROUND & AIMS: Immunity and genetic factors govern the recovery from acute hepatitis C virus (HCV) infection. No predictive factors have been yet identified in patients coinfected with the humanBACKGROUND & AIMS: Immunity and genetic factors govern the recovery from acute hepatitis C virus (HCV) infection. No predictive factors have been yet identified in patients coinfected with the human immunodeficiency virus (HIV). We investigated whether early T cell responses to HCV producing transforming-growth-factor beta (TGF-β) predict the outcome of acute HCV coinfection, independently of the IL-28B gene polymorphism. METHODS: Intracellular cytokine staining assays against HCV-core, E1, NS2, and NS4 overlapping peptides were used for the analysis of peripheral HCV-specific TGF-β-producing T cells. Patients were genotyped for IL-28B polymorphisms. Healthy donors' samples were tested as controls. Twenty-four acute hepatitis C-HIV+ patients were followed-up for 15months defining two groups: (A) Recovered (n=16, 5 spontaneous recoveries, 11 sustained virologic response after treatment), (B) Chronic HCV (n=8, 4 spontaneous chronic course, 4 therapeutic failures). RESULTS: During the acute pretreatment phase, core/NS2-specific TGF-β-producing CD4+ and/or CD8+ T cells were detected in 8/24 (33%) patients. Lack of anti-HCV TGF-β+ cells was characteristic of healthy donors and Group A, except for 2 cases, with frequencies significantly lower than in Group B (p=0.04 and 0.01), and was associated with recovery in 14/16 cases. Presence of anti-HCV TGF-β+ cells was associated with persistent viremia in 6/8 cases (p=0.005). This profile remained stable over time. Such TGF-β production was independent of the rs129679860 SNP (p=1.0) which was not associated with recovery (p=1.0). CONCLUSIONS: During acute hepatitis C, pre-therapeutic HCV-specific TGF-β-producing T cells are a new marker independent of the IL-28B gene polymorphism, predicting the lack of spontaneous or therapeutic HCV clearance.

• A role for CMV-specific CD4+CX3CR1+ T cells and CMV-induced T cell immunopathology in HIV-associated atherosclerosis.

  Authors: Karim Sacre, Peter W Hunt, Priscilla Y Hsue, Ekaterina Maidji, Jeffrey N Martin, Steven G Deeks, Brigitte Autran, Joseph M McCune

  AIDS (London, England). 02/2012;

  OBJECTIVE:: Human Immunodeficiency Virus (HIV)-infected subjects are at increased risk for myocardial infarction. Given observations that CMV infection, CMV-specific T cells and CX3CR1 have each beenOBJECTIVE:: Human Immunodeficiency Virus (HIV)-infected subjects are at increased risk for myocardial infarction. Given observations that CMV infection, CMV-specific T cells and CX3CR1 have each been associated with atherosclerosis, we hypothesized thatCMV-induced T cell immunopathology could contribute to HIV-associated atherosclerosis. METHODS:: We measured the expression of CX3CR1 on peripheral blood mononuclear cells and its association with carotid artery intima-media thickness (IMT) in 29HIV-infected subjects and 48 uninfected controls. We analyzed the phenotype and specificity of CX3CR1 CD4 T cells, the production ofCX3CL1 (the ligand of CX3CR1) by CMV-infected endothelial cells in vitro,and the migration of CD4 T cells induced by CX3CL1. RESULTS:: Theprogression of atherosclerosis in HIV-infected subjects, as assessed by longitudinal measurements of carotid IMT, was associated with a high frequency of CD4 T cells that express the chemokine receptor, CX3CR1. Such CD4CX3CR1 T cells were antigen-primed, produced high levels of pro-inflammatory cytokines, and comprised the majority of the CMV-specific CD4 T cells. CMV-stimulated CD4 T cells were also found to induce the production of CX3CL1 (the ligand for CX3CR1) by human arterial endothelial cells, driving the transendothelial migration of pro-inflammatory CD4 T cells. Finally, we observed that CD4CX3CR1 T cells could be localized to the coronary arterial wall in HIV disease. CONCLUSION:: HIV-associated atherosclerosis may be driven by a positive feedback pathway in which a high frequency of antigen-stimulated, CMV-specific CD4CX3CR1T cells induce endothelial cells to secrete CX3CL1, which itself drives progressive infiltration of the arterial wall by pro-inflammatory cells.

• Escape from highly effective public CD8+ T-cell clonotypes by HIV.

  Authors: Maria Candela Iglesias, Jorge R Almeida, Solène Fastenackels, David J van Bockel, Masao Hashimoto, Vanessa Venturi, Emma Gostick, Alejandra Urrutia, Linda Wooldridge, Mathew Clement [......] Brigitte Autran, Arnaud Moris, Jamie Rossjohn, Miles P Davenport, Masafumi Takiguchi, Christian Brander, Daniel C Douek, Anthony D Kelleher, David A Price, Victor Appay

  Blood. 07/2011; 118(8):2138-49.

  Mapping the precise determinants of T-cell efficacy against viruses in humans is a public health priority with crucial implications for vaccine design. To inform this effort, we performed aMapping the precise determinants of T-cell efficacy against viruses in humans is a public health priority with crucial implications for vaccine design. To inform this effort, we performed a comprehensive analysis of the effective CD8(+) T-cell clonotypes that constitute responses specific for the HIV p24 Gag-derived KK10 epitope (KRWIILGLNK; residues 263-272) restricted by HLA-B*2705, which are known to confer superior control of viral replication in HIV-infected individuals. Particular KK10-specific CD8(+) T-cell clonotypes, characterized by TRBV4-3/TRBJ1-3 gene rearrangements, were found to be preferentially selected in vivo and shared between individuals. These "public" clonotypes exhibit high levels of TCR avidity and Ag sensitivity, which impart functional advantages and enable effective suppression of HIV replication. The early L(268)M mutation at position 6 of the KK10 epitope enables the virus to avoid recognition by these highly effective CD8(+) T-cell clonotypes. However, alternative clonotypes with variant reactivity provide flexibility within the overall KK10-specific response. These findings provide refined mechanistic insights into the workings of an effective CD8(+) T-cell response against HIV.

• CTL escape mediated by proteasomal destruction of an HIV-1 cryptic epitope.

  Authors: Sylvain Cardinaud, Gesa Consiglieri, Romain Bouziat, Alejandra Urrutia, Stéphanie Graff-Dubois, Slim Fourati, Isabelle Malet, Julien Guergnon, Amélie Guihot, Christine Katlama, Brigitte Autran, Peter van Endert, François A Lemonnier, Victor Appay, Olivier Schwartz, Peter M Kloetzel, Arnaud Moris

  PLoS pathogens. 05/2011; 7(5):e1002049.

  Cytotoxic CD8+ T cells (CTLs) play a critical role in controlling viral infections. HIV-infected individuals develop CTL responses against epitopes derived from viral proteins, but also againstCytotoxic CD8+ T cells (CTLs) play a critical role in controlling viral infections. HIV-infected individuals develop CTL responses against epitopes derived from viral proteins, but also against cryptic epitopes encoded by viral alternative reading frames (ARF). We studied here the mechanisms of HIV-1 escape from CTLs targeting one such cryptic epitope, Q9VF, encoded by an HIVgag ARF and presented by HLA-B*07. Using PBMCs of HIV-infected patients, we first cloned and sequenced proviral DNA encoding for Q9VF. We identified several polymorphisms with a minority of proviruses encoding at position 5 an aspartic acid (Q9VF/5D) and a majority encoding an asparagine (Q9VF/5N). We compared the prevalence of each variant in PBMCs of HLA-B*07+ and HLA-B*07- patients. Proviruses encoding Q9VF/5D were significantly less represented in HLA-B*07+ than in HLA-B*07- patients, suggesting that Q9FV/5D encoding viruses might be under selective pressure in HLA-B*07+ individuals. We thus analyzed ex vivo CTL responses directed against Q9VF/5D and Q9VF/5N. Around 16% of HLA-B*07+ patients exhibited CTL responses targeting Q9VF epitopes. The frequency and the magnitude of CTL responses induced with Q9VF/5D or Q9VF/5N peptides were almost equal indicating a possible cross-reactivity of the same CTLs on the two peptides. We then dissected the cellular mechanisms involved in the presentation of Q9VF variants. As expected, cells infected with HIV strains encoding for Q9VF/5D were recognized by Q9VF/5D-specific CTLs. In contrast, Q9VF/5N-encoding strains were neither recognized by Q9VF/5N- nor by Q9VF/5D-specific CTLs. Using in vitro proteasomal digestions and MS/MS analysis, we demonstrate that the 5N variation introduces a strong proteasomal cleavage site within the epitope, leading to a dramatic reduction of Q9VF epitope production. Our results strongly suggest that HIV-1 escapes CTL surveillance by introducing mutations leading to HIV ARF-epitope destruction by proteasomes.

• Elite controllers as a model of functional cure.

  Authors: Brigitte Autran, Benjamin Descours, Véronique Avettand-Fenoel, Christine Rouzioux

  Current opinion in HIV and AIDS. 04/2011; 6(3):181-7.

  The limitations of life-long antiretroviral therapies for the HIV infection lead to a novel concept of a functional cure developing innovative therapeutic strategies to generate a long-term remissionThe limitations of life-long antiretroviral therapies for the HIV infection lead to a novel concept of a functional cure developing innovative therapeutic strategies to generate a long-term remission of HIV replication without treatment. This concept requires an understanding of the mechanisms by which HIV is controlled in conditions of undetectable virus replication, before developing ambitious therapies blocking durably viral replication - and ultimately eradicating HIV. Recent literature shows that the exceptional elite controller status is usually not driven by virus gross genetic defects, despite some virus attenuation resulting from immune selective pressure, but is frequently determined by host's genetic factors permitting robust cell-mediated immunity to control the virus replication and reservoirs. Lack of immunity and immune deficiency can however limit this model in some cases and only a subgroup in whom both the virus and the immune deficiency are controlled, that is the elite long-term controllers, might represent the best current model for a functional cure. This review examines whether the exceptional HIV-infected elite controllers, who spontaneously and durably maintain extremely low virus replication, might be considered as a model for a functional cure and whether the mechanisms identified in these exceptional individuals might serve to identify therapeutic or vaccine strategies.

• Old age and anti-cytomegalovirus immunity are associated with altered T-cell reconstitution in HIV-1-infected patients.

  Authors: Victor Appay, Solène Fastenackels, Christine Katlama, Hocine Ait-Mohand, Luminita Schneider, Amélie Guihot, Michael Keller, Beatrix Grubeck-Loebenstein, Anne Simon, Olivier Lambotte, Peter W Hunt, Steven G Deeks, Dominique Costagliola, Brigitte Autran, Delphine Sauce

  AIDS (London, England). 03/2011; 25(15):1813-22.

  Increasing evidence supports a parallel between HIV-1 infection and immune aging, which is particularly apparent with common changes in naive versus memory T-cell proportions. Here, we aimed atIncreasing evidence supports a parallel between HIV-1 infection and immune aging, which is particularly apparent with common changes in naive versus memory T-cell proportions. Here, we aimed at refining the value of common T-cell-associated markers of immunosenescence during HIV disease progression or aging, and at exploring further the impact in this context of old age as well as cytomegalovirus (CMV) co-infection, which is predominant in HIV-1-infected individuals. Frequencies of naive or CD57(+) memory T cells as well as the magnitude of CMV-pp65 T cells were measured in HIV-1-infected patients grouped according to disease progression status, treatment and age. Our results indicate that the decline in naive T-cell levels rather than the accumulation of CD57(+) senescent T cells identifies best the premature development of an immunosenescence phenotype with HIV disease progression. Moreover, advanced age or mounting of strong CMV-specific responses impact independently on CD4(+) T-cell counts and recovery with antiretroviral therapy. The present findings indicate that HIV-1 infection amplifies the effect of age on naive T-cell levels, and highlight the constraint on the capacity of treated patients to reconstitute their CD4(+) T-cell compartment due to age and CMV co-infection.

• HIV disease progression despite suppression of viral replication is associated with exhaustion of lymphopoiesis.

  Authors: Delphine Sauce, Martin Larsen, Solène Fastenackels, Michèle Pauchard, Hocine Ait-Mohand, Luminita Schneider, Amélie Guihot, Faroudy Boufassa, John Zaunders, Malika Iguertsira [......] Anthony D Kelleher, Anne Simon, Laurence Meyer, Dominique Costagliola, Steven G Deeks, Olivier Lambotte, Brigitte Autran, Peter W Hunt, Christine Katlama, Victor Appay

  Blood. 03/2011; 117(19):5142-51.

  The mechanisms of CD4(+) T-cell count decline, the hallmark of HIV disease progression, and its relationship to elevated levels of immune activation are not fully understood. Massive depletion ofThe mechanisms of CD4(+) T-cell count decline, the hallmark of HIV disease progression, and its relationship to elevated levels of immune activation are not fully understood. Massive depletion of CD4(+) T cells occurs during the course of HIV-1 infection, so that maintenance of adequate CD4(+) T-cell levels probably depends primarily on the capacity to renew depleted lymphocytes, that is, the lymphopoiesis. We performed here a comprehensive study of quantitative and qualitative attributes of CD34(+) hematopoietic progenitor cells directly from the blood of a large set of HIV-infected persons compared with uninfected donors, in particular the elderly. Our analyses underline a marked impairment of primary immune resources with the failure to maintain adequate lymphocyte counts. Systemic immune activation emerges as a major correlate of altered lymphopoiesis, which can be partially reversed with prolonged antiretroviral therapy. Importantly, HIV disease progression despite elite control of HIV replication or virologic success on antiretroviral treatment is associated with persistent damage to the lymphopoietic system or exhaustion of lymphopoiesis. These findings highlight the importance of primary hematopoietic resources in HIV pathogenesis and the response to antiretroviral treatments.

• Long-term nonprogressors and elite controllers in the ANRS CO5 HIV-2 cohort.

  Authors: Rodolphe Thiébaut, Sophie Matheron, Audrey Taieb, Francoise Brun-Vezinet, Geneviève Chêne, Brigitte Autran

  AIDS (London, England). 02/2011; 25(6):865-7.

  Among 342 HIV-2-infected patients of the ANRS CO5 HIV-2 cohort, the prevalence of long-term nonprogressors (LTNPs) (i.e. asymptomatic for at least 8 years while maintaining CD4 cell count at leastAmong 342 HIV-2-infected patients of the ANRS CO5 HIV-2 cohort, the prevalence of long-term nonprogressors (LTNPs) (i.e. asymptomatic for at least 8 years while maintaining CD4 cell count at least 500 cells/μl) and of HIV controllers (i.e. controlling HIV replication in the absence of antiretroviral treatment for at least 10 years) was 6.1% (95% confidence interval 3.9-9.1) and 9.1% (6.3-12.7), respectively. Most LTNPs (81%) were HIV controllers, whereas only 55% of HIV controllers were LTNPs.

• Immune reconstitution after a decade of combined antiretroviral therapies for human immunodeficiency virus.

  Authors: Amélie Guihot, Anne Bourgarit, Guislaine Carcelain, Brigitte Autran

  Trends in immunology. 02/2011; 32(3):131-7.

  The introduction of combined antiretroviral therapies (HAART) has reversed the fatal course of human immunodeficiency virus (HIV) infection. HAART controls virus production and, in most cases, allowsThe introduction of combined antiretroviral therapies (HAART) has reversed the fatal course of human immunodeficiency virus (HIV) infection. HAART controls virus production and, in most cases, allows the quantitative and functional immune defects caused by HIV to be reversed. Here, we review T cell homeostatic mechanisms that drive immune recovery. These homeostatic mechanisms, as well as differences in T cell antigen exposure, explain the distinct patterns of recovery for HIV-specific T cells versus T cells specific for other pathogens. Immune restoration during HAART can, however, have adverse effects. Immune restoration syndrome occurs in some patients as a result of successful but unbalanced immunity.

• A therapeutic dendritic cell-based vaccine for HIV-1 infection.

  Authors: Felipe García, Núria Climent, Lambert Assoumou, Cristina Gil, Nuria González, José Alcamí, Agathe León, Joan Romeu, Judith Dalmau, Javier Martínez-Picado, Jeff Lifson, Brigitte Autran, Dominique Costagliola, Bonaventura Clotet, Josep M Gatell, Montserrat Plana, Teresa Gallart

  The Journal of infectious diseases. 02/2011; 203(4):473-8.

  A double-blinded, controlled study of vaccination of untreated patients with chronic human immunodeficiency virus type 1 (HIV-1) infection with 3 doses of autologous monocyte-derived dendritic cellsA double-blinded, controlled study of vaccination of untreated patients with chronic human immunodeficiency virus type 1 (HIV-1) infection with 3 doses of autologous monocyte-derived dendritic cells (MD-DCs) pulsed with heat inactivated autologous HIV-1 was performed. Therapeutic vaccinations were feasible, safe, and well tolerated. At week 24 after first vaccination (primary end point), a modest significant decrease in plasma viral load was observed in vaccine recipients, compared with control subjects (P = .03). In addition, the change in plasma viral load after vaccination tended to be inversely associated with the increase in HIV-specific T cell responses in vaccinated patients but tended to be directly correlated with HIV-specific T cell responses in control subjects.

• The V1V2 domain and an N-linked glycosylation site in the V3 loop of the HIV-1 envelope glycoprotein modulate neutralization sensitivity to the human broadly neutralizing antibody 2G12.

  Authors: Antoine Chaillon, Martine Braibant, Thierry Moreau, Suzie Thenin, Alain Moreau, Brigitte Autran, Francis Barin

  Journal of virology. 01/2011; 85(7):3642-8.

  The broadly neutralizing human monoclonal antibody 2G12 binds to a carbohydrate-dependent epitope involving three major potential N-linked glycosylation sites (PNGS) of gp120 (N295, N332, and N392).The broadly neutralizing human monoclonal antibody 2G12 binds to a carbohydrate-dependent epitope involving three major potential N-linked glycosylation sites (PNGS) of gp120 (N295, N332, and N392). Through analysis of the sensitivity to 2G12 of pseudotyped viruses carrying envelope proteins from HIV-1 clade B-infected long-term nonprogressors, we selected two naturally occurring env clones with opposite sensitivities to 2G12, albeit harboring the 3 particular PNGS known to be essential for 2G12 binding (N295, N332, and N392). The resistant clone presented a long and potentially heavily glycosylated V1V2 loop and an additional PNGS (N302) in the V3 loop. The sensitive clone harbored a short V1V2 loop and lacked the PNGS at N302. We created chimeric envelope genes by swapping the V1V2 domains of the two env clones. The influence of N302 on 2G12 sensitivity was assessed by PCR-based site-directed mutagenesis. Both the exchange of the V1V2 domain and the introduction of the PNGS at N302 on the 2G12-sensitive clone induced a significant decrease in sensitivity to 2G12. In contrast, the reverse V1V2 exchange and the removal of the PNGS at N302 on the 2G12-resistant clone increased sensitivity to 2G12, confirming the influence of these regions on 2G12 sensitivity. Our results, supported by a molecular-modeling study, suggest that both the V1V2 loop and an additional PNGS in V3 might limit access to the 2G12 epitope.

• Differentiation associated regulation of microRNA expression in vivo in human CD8+ T cell subsets.

  Authors: Bruno Salaun, Takuya Yamamoto, Bassam Badran, Yasuko Tsunetsugu-Yokota, Antoine Roux, Lukas Baitsch, Redouane Rouas, Hussein Fayyad-Kazan, Petra Baumgaertner, Estelle Devevre, Anirudh Ramesh, Marion Braun, Daniel Speiser, Brigitte Autran, Philippe Martiat, Victor Appay, Pedro Romero

  Journal of translational medicine. 01/2011; 9:44.

  The differentiation of CD8+ T lymphocytes following priming of naïve cells is central in the establishment of the adaptive immune response. Yet, the molecular events underlying this process are notThe differentiation of CD8+ T lymphocytes following priming of naïve cells is central in the establishment of the adaptive immune response. Yet, the molecular events underlying this process are not fully understood. MicroRNAs have been recently shown to play a key role in the regulation of haematopoiesis in mouse, but their implication in peripheral lymphocyte differentiation in humans remains largely unknown. In order to explore the potential implication of microRNAs in CD8+ T cell differentiation in humans, microRNA expression profiles were analysed using microarrays and quantitative PCR in several human CD8+ T cell subsets defining the major steps of the T cell differentiation pathway. We found expression of a limited set of microRNAs, including the miR-17~92 cluster. Moreover, we reveal the existence of differentiation-associated regulation of specific microRNAs. When compared to naive cells, miR-21 and miR-155 were indeed found upregulated upon differentiation to effector cells, while expression of the miR-17~92 cluster tended to concomitantly decrease. This study establishes for the first time in a large panel of individuals the existence of differentiation associated regulation of microRNA expression in human CD8+ T lymphocytes in vivo, which is likely to impact on specific cellular functions.

• Maraviroc does not affect humoral response to the pandemic influenza A-H1N1v 2009 adjuvanted vaccine in HIV-1-infected patients.

  Authors: Ana Canestri, Anne Krivine, Lambert Assoumou, Monique Le Corre, Flore Rozenberg, Anne-Geneviève Marcelin, Luminita Schneider, Assia Samri, Guislaine Carcelain, Brigitte Autran, Christine Katlama, Amélie Guihot

  AIDS (London, England). 10/2010; 24(18):2887-9.

  Immune changes induced by the CCR5 antagonist maraviroc raise the question of an impairment of responses to vaccines. We evaluated the immunogenicity of the adjuvanted pandemic influenza A-H1N1v 2009Immune changes induced by the CCR5 antagonist maraviroc raise the question of an impairment of responses to vaccines. We evaluated the immunogenicity of the adjuvanted pandemic influenza A-H1N1v 2009 vaccine in HIV-1-infected patients with suppressed HIV viremia with or without a maraviroc-containing regimen. Seroprotection, seroconversion, and geometric mean titer ratio of specific antibody titers did not differ between groups. These results suggest that maraviroc does not significantly affect the immune response to this adjuvanted vaccine.

• Distinct differentiation profiles of HIV-Gag and Nef-specific central memory CD8+ T cells associated with HLA-B57/5801 and virus control.

  Authors: Jing Xie, Wei Lu, Assia Samri, Dominique Costagliola, Aurélie Schnuriger, Bosco C M da Silva, Catherine Blanc, Martin Larsen, Ioannis Theodorou, Christine Rouzioux, Brigitte Autran

  AIDS (London, England). 09/2010; 24(15):2323-9.

  A superior capacity of controlling HIV has been attributed to CD8(+) T cells directed against HIV-Gag compared to Nef, particularly in the context of some protective human leukocyte antigen (HLA)A superior capacity of controlling HIV has been attributed to CD8(+) T cells directed against HIV-Gag compared to Nef, particularly in the context of some protective human leukocyte antigen (HLA) alleles. To further elucidate this protective effect, we compared the multifunctional and differentiation characteristics of CD8(+) T cells specific for HIV-Gag and Nef in HLA-B57/5801-positive and negative nonprogressors. A head-to-head comparison of CD8(+) T cells specific for HIV-Gag and Nef frequencies, cytokine production and differentiation was conducted, in 11 HLA-B57/5801 and 11 HLA-B57/5801 HIV-infected individuals selected from a cohort of 53 nonprogressors by using IFN-gamma-ELISpot assay and flow cytometry analysis of intracellular cytokine production and differentiation profile. Correlations with HIV parameters were studied. Frequencies of Gag-specific but not of Nef-specific CD8(+) T cells correlated with peripheral blood mononuclear cell (PBMC)-associated HIV-DNA. The HIV-Gag and Nef-specific CD8(+) T cells did not differ for IL-2 production in either HLA-B57/5801 or HLA-B57/5801 individuals. The IFN-gamma-producing Gag-specific CD8(+) T cells in HLA-B57/5801 individuals significantly differed from their Nef-specific counterparts by displaying higher proportions of central memory CD45RACCR7 cells positive for CD27(+). This differentiation pattern was not observed in HLA-B57/5801 individuals. Only these HLA-B57/5801-positive Gag-specific CD27(+) central memory CD8(+) T cells, but not their Nef-specific counterparts, negatively correlated with cell-associated HIV-DNA. HLA-B57/5801 drives a preferential CD27(+) differentiation of central memory CD8(+) T cells directed against HIV-Gag but not Nef that may contribute to the ability of Gag-specific CD8(+) T cells to better control HIV in HLA-B57/5801 nonprogressors.

• Disease progression due to dual infection in an HLA-B57-positive asymptomatic long-term nonprogressor infected with a nef-defective HIV-1 strain.

  Authors: Martine Braibant, Jing Xie, Assia Samri, Henri Agut, Brigitte Autran, Francis Barin

  Virology. 09/2010; 405(1):81-92.

  We describe the case of an HLA-B57-positive long-term nonprogressor in whom we previously showed that PBMCs accumulated HIV-1 subtype B proviruses defective in the env gene. After more than 10 yearsWe describe the case of an HLA-B57-positive long-term nonprogressor in whom we previously showed that PBMCs accumulated HIV-1 subtype B proviruses defective in the env gene. After more than 10 years of control of infection, plasma viremia increased progressively, with a concomitant loss of CD4(+) T cells. By phylogenetic analyses of env, nef, vif, and gag sequences obtained at different time points, we suggest here that this patient was initially infected by a putatively attenuated nef-defective variant and that loss of control was due to superinfection with a fully competent virus belonging to the same clade B. At the time of superinfection, its plasma was unable to efficiently neutralize the superinfecting virus and moderate Gag-specific CD8(+) T-cell responses were observed. This suggests the limited capacity of even a long-lasting natural infection with a nef-deficient HIV-1 strain to elicit immune responses able to prevent and control superinfection with a virus of the same clade.

• Persistent chronic inflammation and infection by Chikungunya arthritogenic alphavirus in spite of a robust host immune response.

  Authors: Jean-Jacques Hoarau, Marie-Christine Jaffar Bandjee, Pascale Krejbich Trotot, Trina Das, Ghislaine Li-Pat-Yuen, Bérengère Dassa, Mélanie Denizot, Elsa Guichard, Anne Ribera, Tawfiq Henni [......] Philippe Morbidelli, Gérard Martigny, Michel Jolivet, Frederick Gay, Marc Grandadam, Hugues Tolou, Vincent Vieillard, Patrice Debré, Brigitte Autran, Philippe Gasque

  Journal of immunology (Baltimore, Md. : 1950). 05/2010; 184(10):5914-27.

  Alphaviruses, including Chikungunya virus (CHIKV), produce a transient illness in humans, but severe forms leading to chronic incapacitating arthralgia/arthritis have been reported by mechanismsAlphaviruses, including Chikungunya virus (CHIKV), produce a transient illness in humans, but severe forms leading to chronic incapacitating arthralgia/arthritis have been reported by mechanisms largely ill-characterized. The pathogenesis of CHIKV was addressed in a prospective cohort study of 49 hospitalized patients from Reunion Island subsequently categorized into two distinct groups at 12 mo postinfection. Comprehensive analyses of the clinical and immunological parameters throughout the disease course were analyzed in either the "recovered" or the "chronic" groups to identify prognostic markers of arthritis-like pathology after CHIKV disease. We found that the chronic group consisted mainly of more elderly patients (>60 y) and with much higher viral loads (up to 10(10) viruses per milliliter of blood) during the acute phase. Remarkably, a rapid innate immune antiviral response was demonstrated by robust dendritic/NK/CD4/CD8 cell activation and accompanied by a rather weak Th1/Th2 cytokine response in both groups. Interestingly, the antiviral immune response witnessed by high levels of IFN-alpha mRNA in PBMCs and circulating IL-12 persisted for months only in the chronic group. CHIKV (RNA and proteins) was found in perivascular synovial macrophages in one chronic patient 18 mo postinfection surrounded by infiltrating NK and T cells (CD4(++) but rare cytotoxic CD8). Fibroblast hyperplasia, strong angiogenesis, tissue lesions given the high levels of matrix metalloproteinase 2, and acute cell death [high cleaved poly(ADP-ribose) polymerase staining] were observed in the injured synovial tissue. These observed cellular and molecular events may contribute to chronic arthralgia/arthritis targeted by methotrexate used empirically for effective treatment but with immunosuppressive function in a context of viral persistence.

• Control of vaccinia virus skin lesions by long-term-maintained IFN-gamma+TNF-alpha+ effector/memory CD4+ lymphocytes in humans.

  Authors: Bénédicte Puissant-Lubrano, Philippe Bossi, Frederick Gay, Jean-Marc Crance, Olivia Bonduelle, Daniel Garin, François Bricaire, Brigitte Autran, Behazine Combadière

  The Journal of clinical investigation. 04/2010; 120(5):1636-44.

  Vaccinia virus (VV) vaccination is used to immunize against smallpox and historically was considered to have been successful if a skin lesion formed at the vaccination site. While antibody responsesVaccinia virus (VV) vaccination is used to immunize against smallpox and historically was considered to have been successful if a skin lesion formed at the vaccination site. While antibody responses have been widely proposed as a correlate of efficacy and protection in humans, the role of cellular and humoral immunity in VV-associated skin lesion formation was unknown. We therefore investigated whether long-term residual humoral and cellular immune memory to VV, persisting 30 years after vaccination, could control VV-induced skin lesion in revaccinated individuals. Here, we have shown that residual VV-specific IFN-gamma+TNF-alpha+ or IFN-gamma+IL-2+ CD4+ lymphocytes but not CD8+ effector/memory lymphocytes expressing a skin-homing marker are inversely associated with the size of the skin lesion formed in response to revaccination. Indeed, high numbers of residual effector T cells were associated with lower VV skin lesion size after revaccination. In contrast, long-term residual VV-specific neutralizing antibody (NAbs) titers did not affect skin lesion formation. However, the size of the skin lesion strongly correlated with high levels of NAbs boosted after revaccination. These findings demonstrate a potential role for VV-specific CD4+ responses at the site of VV-associated skin lesion, thereby providing new insight into immune responses at these sites and potentially contributing to the development of new approaches to measure the efficacy of VV vaccination.

• Changes in T-cell subsets in HIV-HCV-coinfected patients during pegylated interferon-alpha2a plus ribavirin treatment.

  Authors: Marta Massanella, Cristina Tural, Laura Papagno, Elisabet Garcia, Antoni Jou, Margarita Bofill, Brigitte Autran, Bonaventura Clotet, Julià Blanco

  Antiviral therapy. 01/2010; 15(3):333-42.

  We evaluated the effect of different doses of pegylated interferon (PEG-IFN)-alpha2a/ribavirin (RBV) on several T-cell activation markers in HIV-HCV-coinfected patients and their relationship withWe evaluated the effect of different doses of pegylated interferon (PEG-IFN)-alpha2a/ribavirin (RBV) on several T-cell activation markers in HIV-HCV-coinfected patients and their relationship with changes in plasma HCV RNA. Frozen peripheral blood mononuclear cells (PBMCs) from 22 patients receiving two different PEG-IFN-alpha2a schedules were analysed by six-colour flow cytometry. Cell-surface expression of CD38 was quantified. HIV and HCV viral loads, as well as absolute CD4+ and CD8+ T-cell counts, were recorded during the follow up (72 weeks). PEG-IFN-alpha2a/RBV treatment decreased the absolute numbers of CD8+ and CD4+ T-cells. The decrease in CD8+ T-cells was more pronounced, resulting in increased percentages of CD4+ T-cells. Percentages of naive/memory CD4+ T-cell subsets remained unchanged, although the percentage of CD38+CD45RO+ cells significantly increased. By contrast, the CD8+ T-cell compartment significantly reduced the percentage of CD45RO+ cells and HLA-DR+ cells, whereas the percentage of CD38 expressing cells was increased because of a significant increase in cell-surface CD38 expression. Changes in CD8+ T-cells were similar for both PEG-IFN-alpha2a/RBV doses, but high doses induced more severe perturbations in CD4+ T-cells. All changes returned to baseline levels after treatment cessation and, except for the loss of naive CD4+ T-cells, were not associated with virological response. Transient lymphopaenia induced by PEG-IFN-alpha2a/RBV differentially affects T-cell subsets. Activated HLA-DR+ and CD45RO+ cells were selectively reduced in peripheral blood, whereas CD38 expression was up-regulated mainly in memory cells. Increasing PEG-IFN-alpha2a/RBV doses mainly affect CD4+ T-cells but failed to modify clinical outcome.

• Preferential amplification of CD8 effector-T cells after transcutaneous application of an inactivated influenza vaccine: a randomized phase I trial.

  Authors: Behazine Combadière, Annika Vogt, Brice Mahé, Dominique Costagliola, Sabrina Hadam, Olivia Bonduelle, Wolfram Sterry, Shlomo Staszewski, Hans Schaefer, Sylvie van der Werf, Christine Katlama, Brigitte Autran, Ulrike Blume-Peytavi

  PloS one. 01/2010; 5(5):e10818.

  Current conventional vaccination approaches do not induce potent CD8 T-cell responses for fighting mostly variable viral diseases such as influenza, avian influenza viruses or HIV. Following ourCurrent conventional vaccination approaches do not induce potent CD8 T-cell responses for fighting mostly variable viral diseases such as influenza, avian influenza viruses or HIV. Following our recent study on vaccine penetration by targeting of vaccine to human hair follicular ducts surrounded by Langerhans cells, we tested in the first randomized Phase-Ia trial based on hair follicle penetration (namely transcutaneous route) the induction of virus-specific CD8 T cell responses. We chose the inactivated influenza vaccine - a conventional licensed tetanus/influenza (TETAGRIP) vaccine - to compare the safety and immunogenicity of transcutaneous (TC) versus IM immunization in two randomized controlled, multi-center Phase I trials including 24 healthy-volunteers and 12 HIV-infected patients. Vaccination was performed by application of inactivated influenza vaccine according to a standard protocol allowing the opening of the hair duct for the TC route or needle-injection for the IM route. We demonstrated that the safety of the two routes was similar. We showed the superiority of TC application, but not the IM route, to induce a significant increase in influenza-specific CD8 cytokine-producing cells in healthy-volunteers and in HIV-infected patients. However, these routes did not differ significantly for the induction of influenza-specific CD4 responses, and neutralizing antibodies were induced only by the IM route. The CD8 cell response is thus the major immune response observed after TC vaccination. This Phase Ia clinical trial (Manon05) testing an anti-influenza vaccine demonstrated that vaccines designed for antibody induction by the IM route, generate vaccine-specific CD8 T cells when administered transcutaneously. These results underline the necessity of adapting vaccination strategies to control complex infectious diseases when CD8 cellular responses are crucial. Our work opens up a key area for the development of preventive and therapeutic vaccines for diseases in which CD8 cells play a crucial role. Clinicaltrials.gov NCT00261001.