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Abstract Background 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 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. Methods 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. Results 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. Conclusions 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.

Abstract Background Chikungunya fever is an emerging arboviral disease characterized by an algo-eruptive syndrome, inflammatory polyarthralgias, or tenosynovitis that can last for months to years. Up to now, the pathophysiology of the chronic stage is poorly understood. Case presentation We report the first case of CHIKV infection with chronic associated rheumatism in a patient who developed progressive erosive arthritis with expression of inflammatory mediators and persistence of specific IgM antibodies over 24 months following infection. Conclusions Understanding the specific features of chikungunya virus as well as how the virus interacts with its host are essential for the prevention, treatment or cure of chikungunya disease.

Abstract Background The identification of antigens able to differentiate tuberculosis (TB) disease from TB infection would be valuable. Cellular and humoral immune responses to Erp (Exported repetitive protein) – a recently identified M. tuberculosis protein – have not yet been investigated in humans and may contribute to this aim. Methods We analyzed the cellular and humoral immune responses to Erp, ESAT-6, Ag85B and PPD in TB patients, in BCG+ individuals without infection, BCG+ individuals with latent TB infection (LTBI) and BCG- controls. We used lymphoproliferation, ELISpot IFN-γ, cytokine production assays and detection of specific human antibodies against recombinant M. tuberculosis proteins. Results We included 22 TB patients, 9 BCG+ individuals without TB infection, 7 LTBI and 7 BCG- controls. Erp-specific T cell counts were higher in LTBI than in the other groups. Erp-specific T cell counts were higher in LTBI subjects than TB patients (median positive frequency of 211 SFC/106 PBMC (range 118–2000) for LTBI subjects compared to 80 SFC/106 PBMC (range 50–191), p = 0.019); responses to PPD and ESAT-6 antigens did not differ between these groups. IFN-γ secretion after Erp stimulation differed between TB patients and LTBI subjects (p = 0.02). Moreover, LTBI subjects but not TB patients or healthy subjects produced IgG3 against Erp. Conclusion The frequencies of IFN-γ-producing specific T cells, the IFN-γ secretion and the production of IgG3 after Erp stimulation are higher in LTBI subjects than in TB patients, whereas PPD and ESAT-6 are not.

Malignancies represent a major cause of morbidity and mortality in human immunodeficiency virus (HIV)-infected patients. The introduction of combined antiretroviral therapy has modified the spectrum of malignancies in HIV infection with a decreased incidence of acquired immunodeficiency syndrome (AIDS) malignancies such as Kaposi's sarcoma and non- Hodgkin's lymphoma due to partial immune recovery and an increase in non-AIDS-defining malignancies due to prolonged survival. Management of HIV-infected patients with cancer requires a multidisciplinary approach, involving both oncologists and HIV physicians to optimally manage both diseases and drug interactions between anticancer and anti- HIV drugs. The French CANCERVIH group presents here a review and an experience of managing non-AIDS malignancies in HIV-infected individuals. [ABSTRACT FROM AUTHOR]

Objectives The aim of the study was to assess the impact of rapid and sustained viral control produced by combination antiretroviral therapy (c ART) on HIV-associated immune activation and inflammation. Methods 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 (s CD14) levels during 2 years of effective first-line c ART. Biomarker levels before and after c ART 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 c ART were identified by logistic regression. Results 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 c ART initiation [day 0 ( D0)]. At D0, all biomarker levels were higher than in healthy subjects ( P < 0.05). After 2 years of c ART, 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, s CD14 levels did not change significantly (0.18 × 106 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 c ART. Conclusions The rapid and sustained viral suppression produced by first-line c ART reduced IL-6, IP-10 and MIG to normal levels, while s CD14, a marker of monocyte activation, remained elevated. High levels of IP-10 and MIG tended to persist in older patients. [ABSTRACT FROM AUTHOR]

We performed a genome-wide association study comparing a cohort of 144 human immunodeficiency virus (HIV type 1-infected, untreated white long-term nonprogressors (LTNPs) with a cohort of 605 HIV-1-infected white seroconverters. Forty-seven single-nucleotide polymorphisms (SNPs), located from class I to class III major histocompatibility complex (MHC) subregions, show statistical association (false discovery rate, <0.05) with the LTNP condition, among which 5 reached genome-wide significance after Bonferonni correction. The MHC LTNP-associated SNPs are ordered in ≤4 linkage disequilibrium blocks; interestingly, an MHC class III linkage disequilibrium block (defined by the rs9368699 SNP) seems specific to the LTNP phenotype. [ABSTRACT FROM AUTHOR]

INITIO is an open-labelled randomized trial evaluating first-line therapeutic strategies for human immunodeficiency virus-1 (HIV-1) infection. In an immunology substudy a tetanus toxoid booster (TTB) immunization was planned for 24 weeks after initiation of highly active antiretroviral therapy (HAART). All patients had received tetanus toxoid immunization in childhood. Generation of proliferative responses to tetanus toxoid was compared in two groups of patients, those receiving a protease inhibitor (PI)-sparing regimen ( n = 21) and those receiving a PI-containing ( n = 54) regimen. Fifty-two participants received a TTB immunization [PI-sparing ( n = 15), PI-containing ( n = 37)] and 23 participants did not [PI-sparing ( n = 6) or PI-containing ( n = 17)]. Cellular responses to tetanus antigen were monitored by lymphoproliferation at time of immunization and every 24 weeks to week 156. Proportions with a positive response (defined as stimulation index ≥ 3 and Δ counts per minute ≥ 3000) were compared at weeks 96 and 156. All analyses were intent-to-treat. Fifty-two participants had a TTB immunization at median 25 weeks; 23 patients did not. At weeks 96 and 156 there was no evidence of a difference in tetanus-specific responses, between those with or without TTB immunization ( P = 0·2, P = 0·4). There was no difference in the proportion with response between those with PI-sparing or PI-containing regimens at both time-points ( P = 0·8, P = 0·7). The proliferative response to tetanus toxoid was unaffected by initial HAART regimen. Anti-tetanus responses appear to reconstitute eventually in most patients over 156 weeks when treated successfully with HAART, irrespective of whether or not a TTB immunization has been administered. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [Copyright &y& Elsevier]

The aim of this study was to investigate the peripheral blood lymphocyte (PBL) phenotypes and T cell repertoire in patients with HCV infection, with or without mixed cryoglobulinaemia (MC). The patients were: Group 1, 23 patients with HCV infection and MC; Group 2, 14 patients with HCV infection but without MC; Group 3, 10 patients with symptomatic essential MC. Twenty healthy blood donors were used as controls. Blood lymphocyte counts were determined, and flow cytometry was used to measure proportions of B cells (CD19+), natural killer (NK) cells (CD16+ CD56+), T cells (CD3+), CD4+ T cell subsets (memory CD4+ CD45RO+; naive CD4+ CD45RO-; Th0/Th2 CD4+ CD7-; activated CD4+ CD25+), and CD8+ T cell subsets (immunoregulatory CD8+ CD57+; cytotoxic CD8+ S6F1+, activated CD8+ CD25+). Bias in the usage of T cell receptor (TCR) Vβ chains was studied in a subgroup of 10 representative patients of Group 1 using a polymerase chain reaction (PCR) analysis of the Vβ segments with a series of 20 oligonucleotides specific for the Vβ families. The three groups were comparable for blood lymphocyte counts, and we observed no abnormal repartition of the following PBL subsets: T cells (CD3+), CD4+ and CD8+ subpopulations, B cells (CD19+), and the NK cells (CD16+ 56+). In none of the groups could we observe lymphocyte ex vivo activation as assessed by the normal expression of the activation cell markers: CD25 on CD4+ or CD8+ T cells, or CD5 on B cells. The repartition of naive and memory (CD45RO-/RO+) CD4+ T cells was normal and we did not observe any amplification of the CD4+ CD7- T cell subset differentiated in... [ABSTRACT FROM AUTHOR]

Background: Highly active antiretroviral therapy (HAART) decreases viral load and increases CD4 T-cell counts in patients with advanced HIV-1 infection. Whether HAART can improve CD4 T-cell function, and the biological characteristics affecting immune reconstitution, remain unclear. We undertook an open prospective pilot study to address these issues. Both treatment-naïve and previously treated patients were included.Methods: 20 patients (seven naïve, 13 previously treated) were treated with one protease inhibitor and two reverse-transcriptase inhibitors and followed up for 12 months. We measured CD4-cell proliferation in response to cytomegalovirus and tuberculin antigens and counted subsets of CD4 cells at baseline and months 1, 3, 6, 9, and 12. Patients who had no antigen-specific reactivity at baseline but developed it while receiving HAART were classified as immunological responders.Findings: Four patients had antigen-specific reactivity at baseline compared with 14 at month 12 (p <0.001). Between month 3 and month 12 viral load fell by a median of 1.5 log copies/mL from baseline (4.6 log copies/mL) and CD4-cell count increased by a median of 63/microL (from 93/microL). Ten patients (six of seven naïve, four of 13 previously treated) were immunological responders. They differed significantly from the ten non-responders in that their viral-load reduction was sustained for 12 months, the increase in CD4 count was greater, and they showed an early increase in memory CD4 T cells with an increase of naïve T cells.Interpretation: HAART can induce sustained recovery of CD4 T-cell reactivity against opportunistic pathogens in severely immunosuppressed patients. This recovery depends not on baseline values but on the amplitude and duration of viral-load reduction and the increase of memory CD4 T cells. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

An abstract of the conference paper "Cellular immune responses and changes in VL after a Dendritic Cells (DC)-based therapeutic vaccine in cART treated chronic HIV-infected patients with CD4 T cells above 450/mm," by A. C. Guardo and colleagues are presented.

Human immunodeficiency virus 1 (HIV-1) infection is characterized by a dynamic and persistent state of viral replication that overwhelms the host immune system in the absence of antiretroviral therapy (ART). The impact of prolonged treatment on the antiviral efficacy of HIV-1-specific CD8 + T cells has nonetheless remained unknown. Here, we used single-cell technologies to address this issue in a cohort of aging individuals infected early during the pandemic and subsequently treated with continuous ART. Our data showed that long-term ART was associated with a process of clonal succession, which effectively rejuvenated HIV-1-specific CD8 + T cell populations in the face of immune senescence. Tracking individual transcriptomes further revealed that initially dominant CD8 + T cell clonotypes displayed signatures of exhaustion and terminal differentiation, whereas newly dominant CD8 + T cell clonotypes displayed signatures of early differentiation and stemness associated with natural control of viral replication. These findings reveal a degree of immune resilience that could inform adjunctive treatments for HIV-1., (© 2024. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Therapeutic monoclonal antibodies have been successful in protecting vulnerable populations against SARS-CoV-2. However, their effectiveness has been hampered by the emergence of new variants. To adapt the therapeutic landscape, health authorities have based their recommendations mostly on in vitro neutralization tests. However, these do not provide a reliable understanding of the changes in the dose-effect relationship and how they may translate into clinical efficacy. Taking the example of EvusheldTM (AZD7442), we aimed to investigate how in vivo data can provide critical quantitative results and project clinical effectiveness. We used the Golden Syrian hamster model to estimate 90 % effective concentrations (EC90) of AZD7442 in vivo against SARS-CoV-2 Omicron BA.1, BA.2 and BA.5 variants. While our in vivo results confirmed the partial loss of AZD7442 activity for BA.1 and BA.2, they showed a much greater loss of efficacy against BA.5 than that obtained in vitro. We analyzed in vivo EC90s in perspective with antibody levels measured in a cohort of immunocompromised patients who received 300 mg of AZD7442. We found that a substantial proportion of patients had serum levels of anti-SARS-CoV-2 spike protein IgG above the estimated in vivo EC90 for BA.1 and BA.2 (21 % and 92 % after 1 month, respectively), but not for BA.5. These findings suggest that AZD7442 is likely to retain clinical efficacy against BA.2 and BA.1, but not against BA.5. Overall, the present study illustrates the importance of complementing in vitro investigations by preclinical studies in animal models to help predict the efficacy of monoclonal antibodies in humans., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

The International Patient Organisation for Primary Immunodeficiencies (IPOPI) held its second Global Multi-Stakeholders' Summit, an annual stimulating and forward-thinking meeting uniting experts to anticipate pivotal upcoming challenges and opportunities in the field of primary immunodeficiency (PID). The 2023 summit focused on three key identified discussion points: (i) How can immunoglobulin (Ig) therapy meet future personalized patient needs? (ii) Pandemic preparedness: what's next for public health and potential challenges for the PID community? (iii) Diagnosing PIDs in 2030: what needs to happen to diagnose better and to diagnose more? Clinician-Scientists, patient representatives and other stakeholders explored avenues to improve Ig therapy through mechanistic insights and tailored Ig preparations/products according to patient-specific needs and local exposure to infectious agents, amongst others. Urgency for pandemic preparedness was discussed, as was the threat of shortage of antibiotics and increasing antimicrobial resistance, emphasizing the need for representation of PID patients and other vulnerable populations throughout crisis and care management. Discussion also covered the complexities of PID diagnosis, addressing issues such as global diagnostic disparities, the integration of patient-reported outcome measures, and the potential of artificial intelligence to increase PID diagnosis rates and to enhance diagnostic precision. These proceedings outline the outcomes and recommendations arising from the 2023 IPOPI Global Multi-Stakeholders' Summit, offering valuable insights to inform future strategies in PID management and care. Integral to this initiative is its role in fostering collaborative efforts among stakeholders to prepare for the multiple challenges facing the global PID community., Competing Interests: This study received funding from CSL Behring, Grifols and Takeda. The funder had the following involvement with the study: Company representatives contributed to the stakeholder discussions and reviewed the manuscript. All authors declare no other competing interests. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Van Coillie, Prévot, Sánchez-Ramón, Lowe, Borg, Autran, Segundo, Pecoraro, Garcelon, Boersma, Silva, Drabwell, Quinti, Meyts, Ali, Burns, van Hagen, Pergent and Mahlaoui.)