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G Antoni,
J Guergnon,
C Meaudre,
A Samri,
F Boufassa,
C Goujard,
O Lambotte, B Autran,
C Rouzioux,
D Costagliola,
L Meyer,
I Theodorou
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ABSTRACT: INTRODUCTION:: HLA class I-driven long-term protection against HIV-1 is mainly associated with HLA-B*27 and -B*57. This effect is observed early after infection. Clarification needs to be established concerning the moment of action for the other HLA-B or HLA-C alleles. METHODS:: HLA-B and -C alleles from 111 individuals that control HIV-1 disease for over 8 years and from 747 seroconverters frequencies were compared. Also, HLA-B and HLA-C influence on early levels of plasma HIV-RNA, cellular HIV-DNA, CD4, CD8 and CD4/CD8 ratio was evaluated among the seroconverters. We performed univariate, multivariate and haplotypic analyses in order to disentangle the respective contribution of the HLA-B and HLA-C genes. RESULTS:: The haplotypes analysis shows three patterns of protective effects of HLA-B and HLA-C alleles or haplotypes. (1) The HLA B*57, HLA-B*27, HLA-B*13 and HLA-C*14 alleles, which have a strong effect on long-term disease control, also influence at least one of the early infection phenotypes. (2) HLA-B*52 has a strong effect during early time points on HIV-RNA without significant effect on the long-term control of HIV-1. (3) Finally the HLA-B*14-C*08 haplotype has a strong effect on the long-term protection, without influencing early viral control. CONCLUSIONS:: Our study highlighted independent effects of HLA-B and HLA-C alleles on HIV disease progression. Furthermore, some alleles appeared to be specifically associated with either long-term control or early virological parameters, suggesting different immunological mechanisms according to the disease stages.
AIDS (London, England) 03/2013; · 4.91 Impact Factor
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L. Papagno,
G. Alter,
L. Assoumou,
R. L. Murphy,
F. Garcia,
B. Clotet,
M. Larsen,
M. Braibant,
A. G. Marcelin,
D. Costagliola,
M. Altfeld,
C. Katlama, B. Autran
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ABSTRACT: BACKGROUND: HIV-specific T-cell-based vaccines have been extensively studied in both prevention and therapeutic settings, with most studies failing to show benefit, and some suggesting harm. We previously performed a multicenter, double-blind, placebo-controlled phase II clinical trial in which 65 antiretroviral-treated patients were randomized to receive an HIV-1 recombinant canarypox vaccine (vCP1452) or placebo, followed by analytical treatment interruption. Patients exposed to vaccine had higher levels of viral replication and more rapid time to treatment resumption. OBJECTIVE: In the present study we report the results from extensive immunological investigations to test whether the preferential expansion of HIV-specific CD4(+), rather than CD8(+) T cells, could account for these unexpected results. METHODS: Polychromatic flow cytometry was used to characterize the functional and phenotypic profile of antigen-specific CD8(+) and CD4(+) T cells induced by the immunization. RESULTS: We found a significant increase in HIV-specific CD4(+) T cells producing IFN-gamma and IL-2 in the 4 injections arm compared to the placebo arm following vaccination. In contrast, no difference was observed following vaccination in the phenotype and functional capacity within the CD8(+) T-cell compartment. Neither HLA biases, nor immune hyper-activation, or Env-specific facilitating antibodies were associated with the enhanced virus rebound observed in vaccinees. CONCLUSION: Our data suggest that a vaccine-induced transient activation of HIV-specific CD4(+) but not CD8(+) T cells may have a detrimental effect on HIV outcomes. These findings may provide a mechanistic basis for higher rates of HIV acquisition or replication that have been associated with some T-cell vaccines.
AIDS. 01/2011; 25(1):27-36.
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Retrovirology. 01/2009;
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J Xie,
W Lu,
A Samri,
D Costagliola,
A Schnuriger,
da Silva BC,
C Blanc,
M Almeida,
O Pellé,
I Theodorou,
C Rouzioux, B Autran
Retrovirology. 01/2009;
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ABSTRACT: Bioterrorism is defined by the intentional or threatened of microorganisms or toxins derived from living organisms to cause death or diseases in humans, animals or plants on which we depend. The other major point is to generate fear in the population. More than 180 pathogens have been reported to be potential agents for bioterrorism. The following is an overview of several agents that could be involved in a biological attack.
Cellular and Molecular Life Sciences CMLS 11/2006; 63(19-20):2196-212. · 6.57 Impact Factor
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ABSTRACT: Bioterrorism is defined by the intentional or threatened of microorganisms or toxins derived from living organisms to cause
death or diseases in humans, animals or plants on which we depend. The other major point is to generate fear in the population.
More than 180 pathogens have been reported to be potential agents for bioterrorism. The following is an overview of several
agents that could be involved in a biological attack.
Cellular and Molecular Life Sciences CMLS 09/2006; 63(19):2196-2212. · 6.57 Impact Factor
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A Samri,
C Durier,
A Urrutia,
I Sanchez,
H Gahery-Segard,
S Imbart,
M Sinet,
E Tartour,
J-P Aboulker, B Autran,
A Venet
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ABSTRACT: The gamma interferon (IFN-gamma) enzyme-linked immunospot (ELISPOT) assay is a reference method for the ex vivo monitoring of antigen-specific T cells and a primary tool for assessing clinical trials of human immunodeficiency virus (HIV) or cancer vaccines. Four experienced laboratories in Paris compared their results with this method by exchanging frozen blood samples from eight HIV-seronegative and eight HIV-seropositive subjects. Each laboratory measured the IFN-gamma-producing cells specific for HIV, Epstein-Barr virus, cytomegalovirus, and influenza using the same set of peptides and the same ELISPOT reader but its own ELISPOT technique. The cutoff values for positive responses (50 or 100 spot-forming cells/10(6) peripheral blood mononuclear cells over background) were consistent with the binomial statistic criterion. The global qualitative concordance, as assessed by the kappa index, ranged from 0.38 to 0.92, that is, moderate to excellent, and was better for non-HIV 9-mer peptide pools than for HIV 15-mer peptide pools. The interlaboratory coefficient of variation for the frequency of virus-specific T cells was 18.7% (data are expressed on a log scale). Clustering analysis of HIV-positive subjects showed qualitative agreement for ELISPOT results from all four laboratories. Overall, the good interlaboratory qualitative concordance of IFN-gamma ELISPOT assays with only the peptide source and ELISPOT reader in common suggests that a qualitative comparison of interlaboratory findings is feasible. Nonetheless, a single set of standard operating procedures should be used in multicenter trials to improve standardization.
Clinical and Vaccine Immunology 07/2006; 13(6):684-97. · 2.55 Impact Factor
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ABSTRACT: Cytotoxic T lymphocytes (CTLs) play an essential role in the control of viral replication during human immunodeficiency virus (HIV) infection. However, the efficacy of the CTL response varies between individuals. We tested the hypothesis that genetic polymorphisms in the lytic effector molecule perforin could influence the progression of HIV infection. The perforin gene was screened for single nucleotide polymorphisms (SNPs) by denaturing high-performance liquid chromatography (dHPLC). Correlations were sought between perforin genotype, perforin expression and lytic function of CD8+ T lymphocytes from HIV-positive patients. Association of perforin genotype with disease progression was investigated in 426 seroconverters enrolled in the French SEROCO cohort. AIDS-free survival curves were constructed using the Kaplan-Meier method and compared using the log-rank test. Three SNPs were found in the proximal promoter region of the perforin gene: 63G (allelic frequency 0.029), 112G (allelic frequency 0.071) and 1012T (allelic frequency 0.070). The presence of the 1012T genotype correlated with fewer perforin+ cells among circulating CD8+ CTL. However, CTL lines from HIV(-positive) individuals heterozygous for the perforin 1012T SNP displayed normal lysis of target cells, and within the SEROCO cohort, patients heterozygous for the 1012T SNP showed normal disease progression. However, 1012T/T homozygotes showed a tendency towards slower disease progression (P = 0.08). In conclusion, polymorphism in the perforin gene is limited, and although the 1012T genotype appears to influence perforin expression, it was not conclusively associated with disease progression in HIV infection.
International Journal of Immunogenetics 05/2006; 33(2):73-9. · 1.29 Impact Factor
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A. Schnuriger,
S. Dominguez,
M. Valantin,
R. Tubiana,
J. Gohsn,
A. Simon,
D. Bollens,
P. Campas,
P. Bonnard,
L. Slama, B. Autran,
V. Thibault
Journal of Clinical Virology - J CLIN VIROL. 01/2006; 36.
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ABSTRACT: The use of the smallpox virus as a biological weapon is very old. Confronted with a high probability of a current bioterrorist menace, counteracting strategies have been developed. One of the principle aims relies on the vaccination of teams dedicated to the management of persons infected and the stocking of vaccine for the whole population of a country. Following worldwide eradication of the disease, preventive vaccination was topped in 1978 in France for the primo-vaccination, and in 1984 for repeat vaccinations. The various strains used in the first generation vaccinations are weakened living vaccine, the natural host and origin of which is unknown. Second and third generations vaccines are under study; the principle objective is to obtain efficacy with a minimum of side effects. There are two types of adverse events, generally observed with the first generation vaccines: the first, extremely rare, can be life-threatening; the others, more frequent (10 to 15% of patients) are benign. In emergency situations, in the presence of smallpox, there should be no absolute contraindications to vaccination. In the bioterrorist context, massive vaccination campaigns of the population are unadvisable (because of the considerable risk of death and severe adverse events) in the absence of any real permit, in each case, definition of the vaccinal strategy to be adopted.
La Presse Médicale 02/2005; 34(2 Pt 2):177-184. · 0.67 Impact Factor
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N Alatrakchi,
C Duvivier,
D Costagliola,
A Samri,
A G Marcelin,
G Kamkamidze,
M Astriti,
R Agher,
V Calvez, B Autran,
C Katlama
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ABSTRACT: It is unclear how stable low-level viral replication and CD4 cell numbers can be maintained under highly active antiretroviral therapy (HAART). This study was designed to analyse whether HIV-specific responses in stable partially controlled patients during antiretroviral therapy (ART) differ from those observed in complete HAART failure and whether they contribute to the control of viral load (VL).
Three groups of patients were selected according to plasma HIV RNA levels during 18 months of ART: persistently low VL (LoVL; HIV RNA <10,000 copies/ml; n = 28), undetectable VL (UnVL; HIV RNA <200 copies/ml; n = 29) and high VL (HiVL; HIV RNA >10,000 copies/ml; n = 14). T-cell responses were studied using lymphoproliferative and interferon (IFN)-gamma-ELISpot assays against HIV-p24, -gp160, recall antigens, and 15 pools of HIV-(Gag + RT) peptides.
Frequencies of IFN-gamma-producing CD4 T cells against HIV-p24 were higher in LoVL than in UnVL or HiVL groups [median, 131, 47 and 23 spot-forming cells (SFC)/1 x 10 peripheral blood mononuclear cells (PBMC), respectively; P = 0.012 and P = 0.047]. Lymphoproliferative responses to HIV-p24 and recall antigens were similar in LoVL and UnVL groups but lower in HiVL (P = 0.004). Frequencies of HIV-specific CD8 T cells were higher in LoVL than in UnVL (1340 versus 410 SFC/1 x 10 PBMC; P = 0.001). They correlated negatively with VL in the LoVL and HiVL (r, -0.393, P = 0.039 and r, -0.643, P = 0.024, respectively) and positively correlated with anti-HIV CD4 cell frequencies in the LoVL group only (r, 0.420; P = 0.026).
Persistently low viral replication (<10,000 copies/ml) during ART stimulates high frequencies of HIV-specific CD4 and CD8 T cells compared to full virus suppression or complete ART failure. The association of high anti-HIV activity with large numbers of HIV-specific CD8 T cells contribute to the control of viral replication.
AIDS 02/2005; 19(1):25-33. · 6.24 Impact Factor
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ABSTRACT: Smallpox is among the most dangerous pathogens that could be used by bioterrorists. The former vaccines produced by scarification on the flanks of calves or sheep could be used to protect the whole French population when used with bifurcated needles. They should be replaced by a second-generation vaccine grown in cell culture and, eventually later by new and safer third-generation vaccines using non-replicative viral strains.
Médecine et Maladies Infectieuses 02/2004; 34(1):20-7. · 0.72 Impact Factor
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ABSTRACT: HIV-specific cytotoxic CD8(+) T-lymphocytes (CTL) appear to be the cornerstone of the immune response to HIV infection. Recent studies show that CTL activity reflects patients' anti-HIV immune status and slows disease progression. However, the dynamics of the diversity of this response also appears as a key parameter for immune control but the dynamics of this diversity is largely undocumented. We modelled changes in CTL responses against the seven principal HIV proteins over time. We also studied the influence of plasma viral load on temporal changes in HIV protein recognition by memory CTL. The generic model we developed is based on a continuous time homogeneous Markov process with reversible states. Those states are defined by the number of proteins recognized by memory CTL in a given patient at a given time. This approach was developed within a Bayesian framework. Full Bayesian inference is implemented using Markov chain Monte Carlo simulations (MCMC). The Gibbs sampling algorithm was used to estimate the marginal posterior distributions of the transition intensities between stages of CTL responses. We applied our model to data of 152 HIV-infected patients included in the IMMUNOCO cohort. The model suggested that the diversity of HIV protein recognition by memory CTL in treatment-naive patients decreases as the disease progresses. Namely, the loss of T cytotoxic responses is globally faster than their acquisition. Indeed, these patients' T cytotoxic responses were characterized by marked individual turnover and a gradual loss of multiple protein recognition over time, this loss accelerating as viral load increased.
Statistics in Medicine 06/2003; 22(10):1675-90. · 1.88 Impact Factor
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ABSTRACT: Several methods are now available to evaluate the frequencies of virus-specific CD8 T cells but require a systematic comparison to help at choosing the best strategy for evaluation. First, we compared the ELISpot-IFNgamma assay, intracellular IFNgamma staining and HLA class I tetramer-binding assay to quantify the HIV-specific CD8 T cells. Second, we determined the frequency of recognition of HIV antigens and evaluated whether the mode of antigen presentation might influence the results: We compared HIV antigen presentation in the same ELISpot-IFNgamma assays by using recombinant vaccinia viruses (rVVs) encoding for HIV-LAI Gag, Pol, Env, Nef, Tat and Vif proteins, or a panel of 49 synthetic 8-11 amino acid length peptides tested either individually or pooled. Third, we compared the antigens recognized by memory CTL analysis using chromium release assay (CRA) on CTL lines and by effector CD8 cell analysis using ELISpot assay. Our results show that: (1) Flow cytometry and ELISpot assay measuring IFNgamma production give the same frequency of HIV-specific CD8 T cells; (2) tetramer-binding assay detects more HIV-specific CD8 T cells than other methods; (3) pools of optimal peptides and sum frequencies of individual optimal peptides give similar results in ELISpot assay; (4) ELISpot assays using peptides are more sensitive than those using rVV; and (5) CRA and ELISpot assay when using rVV provide a comparable profile of HIV antigen recognition by memory CTLs (CRA) and effector CTLs (ELISpot) in two thirds cases. These results have important implications for the choice of immunological methods to evaluate CD8 T cells responses to vaccines.
Journal of Immunological Methods 02/2003; 272(1-2):23-34. · 2.20 Impact Factor
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C Delaugerre,
M A Valantin,
M Mouroux,
M Bonmarchand,
G Carcelain,
C Duvivier,
R Tubiana,
A Simon,
F Bricaire,
H Agut, B Autran,
C Katlama,
V Calvez
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ABSTRACT: Antiretroviral treatment interruption in 20 extensively pre-treated HIV-1 patients with treatment failure led to genotype viral reversion of at least one class of drug-mutation resistance in half of the patients. The only predictive factor of reversion was found to be the duration of interruption. The outgrowth of residual wild-type virus seems not to be a true genetic reversion because drug mutations are detected rapidly at salvage therapy re-initiation.
AIDS 12/2001; 15(16):2189-91. · 6.24 Impact Factor
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ABSTRACT: The helper T type 1 (Th1) function of CD4(+) T lymphocytes is presumed to be of key importance in host defense against HIV-1. As the production of different antibody isotypes is dependent on this helper T function, we investigated whether HIV-1-specific responses of a particular IgG isotype could be a reliable marker of long-term HIV-1 control. Assessment of the IgG subclass distribution in the plasma of HIV-1-infected patients enrolled in the French prospective Asymptomatic Long-Term (ALT) cohort showed that IgG2 directed against HIV-1 Env gp41 and Gag proteins was associated with low viral load, high CD4(+) lymphocyte count, and weak neutralizing activity. By contrast, levels of anti-Env and anti-Pol IgG1 as well as the magnitude of neutralizing activity were correlated with the viral load and thus merely reflect the level of HIV replication. Furthermore, IgG2 directed against Gag proteins was significantly associated with HIV-1 p24-specific Th1 cell production of interferon gamma and interleukin 2. In multivariate analysis, only two variables, anti-gp41 IgG2 and plasma HIV-1 RNA, were found to be independent prognostic factors of remaining long-term nonprogressive over time. By providing new insight into the nature of an HIV-specific antibody response associated with the control of virus replication, these findings have implications for the design of HIV vaccines.
AIDS Research and Human Retroviruses 11/2001; 17(15):1435-46. · 2.25 Impact Factor
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ABSTRACT: Immune reconstitution during antiretroviral therapy has recently been shown to depend upon multiple factors at work in T cell homeostasis, amongst which the reduction of thymus dysfunction and of immune hyperactivation are instrumental. The optimism that has been raised by the restoration of hosts' defenses against opportunistic pathogens is, however, balanced by the poor immunity restored against HIV; thus, innovative immune interventions are required.
Current Opinion in Immunology 09/2001; 13(4):483-8. · 9.52 Impact Factor
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ABSTRACT: Although the mouse spleen dendritic cell (DC) is perhaps the most intensively studied DC type, little has been published concerning its human equivalent. In this report, rare event flow cytometry and in situ immunofluorescence were used to study the surface phenotype and distribution of HLA-DR(+) CD3(-)14(-)16(-)19(-) human spleen DC. Spleens from organ donors with different clinical histories were used. Most (81% +/- 9%; n = 14) spleen DCs expressed high levels of the integrin CD11c. CD11c(+) DCs were distributed in 3 distinct regions-the peri-arteriolar T-cell zones, the B-cell zones, and the marginal zone, where they formed a ring of cells surrounding the white pulp, just inside a ring of CD14(+) red pulp macrophages, apparently more regularly organized than the previously described marginating DC population in the mouse spleen. The T-cell zones contained CD86(+) DCs, among which a subpopulation expressed CD83. These mature/activated CD86(+) DCs represented a minority (12% +/- 8%) of total spleen DCs in most organ donors: most spleen DCs are immature. In 3 of 18 (17%) donors, however, most (54%-81%) of spleen DCs were CD86(+), suggesting that in vivo DC activation had occurred. In one donor, a radical shift in DC distribution from the marginal zone to the T-cell zones was also observed. This activation of spleen DCs in vivo was reminiscent of the effects of experimental microbial product injection in mice, and it seemed to correlate with bacterial infection or multiple trauma. (Blood. 2001;97:3470-3477)
Blood 07/2001; 97(11):3470-7. · 9.90 Impact Factor
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ABSTRACT: Human immunodeficiency virus (HIV) infection is characterized by the massive infiltration of secondary lymphoid organs with activated CD8(+) T lymphocytes. While converging data indicated that these cells were HIV-specific cytotoxic T lymphocytes (CTLs) responsible for HIV spread limitation, direct evidence was lacking. Here, the presence of HIV-specific effector CTLs was demonstrated directly ex vivo in 15 of 24 microdissected splenic white pulps from an untreated patient and in 1 of 24 tonsil germinal centers from a second patient with incomplete viral suppression following bitherapy. These patients had plasma HIV RNA loads of 5900 and 820 copies per milliliter. The frequencies of HIV-1 DNA(+) cells in their lymphoid organs were more than 1 in 50 and 1 in 175, respectively. Spliced viral messenger RNA (a marker for ongoing viral replication) was present in most immunocompetent structures tested. Conversely, CTL activity was not found in spleens from 2 patients under highly active antiretroviral therapy, with undetectable plasma viral load. These patients had much lower spleen DNA(+) cell frequencies (1 in 2700 and 1 in 3800) and no white pulps containing spliced RNA. CTL effector activity as well as spliced viral messenger RNA were both concentrated in the white pulps and germinal centers. This colocalization indicates that viral replication in immunocompetent structures of secondary lymphoid organs triggers anti-HIV effector CTLs to these particular locations, providing clues to target therapeutic intervention.
Blood 06/2001; 97(9):2695-701. · 9.90 Impact Factor
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Advances in experimental medicine and biology 02/2001; 495:205-12. · 1.09 Impact Factor
