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Intramuscular long-acting antiretroviral drugs can improve adherence to lifelong antiretroviral treatment. Nevertheless, adipose tissue thickness and distribution play a critical role with injectable drugs. We describe a virological failure with cabotegravir and rilpivirine in a Black African woman with human immunodeficiency virus type 1 with gynoid fat distribution (ie, adipose tissue prevailing in the pelvis and hip area) and body mass index

Mpox virus (MPXV) caused a multi-country outbreak in non-endemic areas in 2022. The Modified Vaccinia Ankara (MVA)-based vaccine was used as prophylaxis, but its effectiveness remains poorly characterized. Here, we developed two assays for quantification of neutralizing antibodies (NAbs), using MVA-GFP or a recently isolated MPXV. We measured NAb levels in 470 sera from control, MPXV-infected or MVA-vaccinated individuals. Various levels of MVA NAbs were detected after infection, historic smallpox or MVA vaccination. MPXV was barely sensitive to neutralization. Addition of complement enhanced detection of responsive individuals and NAb levels. Anti-MVA and -MPXV NAbs were observed in 94% and 82% of infected individuals, respectively, and 92% and 56% of MVA vaccinees, respectively. NAb titers were higher in individuals born before 1980, highlighting the impact of historic smallpox vaccination on humoral immunity. Altogether, our results indicate that MPXV neutralization is complement-dependent and help uncover the mechanisms underlying vaccine effectiveness.SUMMARYIn 2022, mpox virus (MPXV) caused an unprecedented pandemic outbreak in non-endemic areas. The efficacy of currently available third generation MVA-based vaccines and the nature of the humoral response generated after MPXV infection remain poorly characterized. We established cell-based assays to measure neutralizing antibodies (NAbs) targeting MVA or MPXV. We analyzed 470 sera and detected robust levels of MVA NAbs after infection, historic smallpox vaccination or administration of MVA-based vaccines. Efficient MPXV neutralization required addition of complement. High NAb titers were measured in ancient smallpox-vaccinated MPXV-infected patients, suggesting a potential cross-protection mediated by hybrid immunity.

The persistence of a leaky gut in HIV-treated patients leads to chronic inflammation with increased rates of cardiovascular, liver, kidney, and neurological diseases. Tissue regulatory T (tTreg) cells are involved in the maintenance of intestinal homeostasis and wound repair through the IL-33 pathway. In this study, we investigated whether the persistence of gut mucosal injury during HIV infection might be explained in part by a flaw in the mechanisms involved in tissue repair. We observed an increased level of IL-33 in the gut of HIV-infected patients, which is associated with an increased level of fibrosis and a low peripheral reconstitution of CD4+ T cells. Our results showed that intestinal Treg cells from HIV-infected patients were enriched in tTreg cells prone to support tissue repair. However, we observed a functional defect in tTreg cells caused by the lack of amphiregulin secretion, which could contribute to the maintenance of intestinal damage. Our data suggest a mechanism by which the lack of amphiregulin secretion by tTreg may contribute to the lack of repair of the epithelial barrier.

Most people living with HIV need antiretroviral therapy to control their infection and experience viral relapse in case of treatment interruption, because of viral reservoir (proviruses) persistence. Knowing that proviruses are very diverse and most of them are defective in treated individuals, we aimed to characterize the HIV blood reservoirs of posttreatment controllers (PTCs), rare models of drug-free remission, in comparison with spontaneous controllers and treated individuals.

Background We evaluated the immune response to COVID-19 vaccines in several specific populations at high risk of severe COVID-19. Methods Participants from the French national multi-center prospective cohort study ANRS0001S COV-POPART were included (11 specific subpopulations: and 2 control groups (18–64 years and over 65 years)). In this preliminary analysis patients and controls who had received at least two vaccine doses have been included. Percentages (95% confidence intervals (CI)) of participants with anti-Spike SARS-CoV-2 IgG antibodies (ELISA) and specific neutralizing antibodies (in vitro neutralization assay) were evaluated at one month after the second dose of COVID-19 vaccine. Results 3703 were included: 2650 participants from specific subpopulations (171 solid cancers, 160 SOT, 100 HCT, 91 chronic renal failures, 141 systemic autoimmune diseases, 157 autoimmune inflammatory rheumatic diseases, 361 multiple sclerosis (MS) or neuromyelitis optica spectrum disorders, 61 hypogammaglobulinemia, 401 diabetic, 739 obeses non-diabetic and 476 HIV) and 1053 controls (893: 18–64 years and 160 over 65 years). Median age was 51.7 years [InterQuartile range: 40.8 – 60.9] and 50.7% were male. Most of the participants received BNT162b2 vaccine (86.4%). In the control group, 100% (95%CI: 99.6;100.0) of those aged 18–64 and 99.4% (96.6; 100.0) of those over 65 years developed anti-Spike IgG antibodies. PLWHIV, cancer and diabetic patients had high rate of responders after two doses with 98.3% (97.2;99.1), 93.0% (88.1;96.3) and 92.0% (88.9;94.5), respectively. The lowest percentage of responders was found in patients with SOT (13.8% (8.8;20.1), HSCT (34.0% (24.8;44.2) and hypogammaglobulinemia (52.5% 39.3;65.4). In both control groups, the frequency of neutralizing antibodies was similar to the anti-Spike IgG antibody response. In the immunodeficient populations, neutralizing antibodies responders tended to be less frequent than anti-Spike antibodies responders. Similar trends than for IgG antibody were identified (Figure 1). Anti-Spike and Neutralizing antibody (Ab) responses (95% CI) one month after the second dose of COVID-19 vaccine in specific and control populations. Conclusion Lower COVID-19 vaccine humoral response was observed in specific populations than in controls, especially in patients with hypogammaglobulinemia, HSCT and SOT. Disclosures Paul LOUBET, MD, PhD, pfizer: Board Member Odile Launay, MD, PhD, AstraZeneca: Financial|GlaxoSmithKline: Advisor/Consultant|GlaxoSmithKline: Grant/Research Support|Johnson & Johnson: Advisor/Consultant|Johnson & Johnson: Grant/Research Support|MD: Advisor/Consultant|Moderna: Advisor/Consultant|MSD: Data safety monitoring board|Pfizer: Advisor/Consultant|Pfizer: Grant/Research Support|Sanofi Pasteur: Advisor/Consultant|Sanofi Pasteur: Grant/Research Support|Sanofi Pasteur: Data safety monitoring board.

Background Deciding how best to invest in healthcare is never an easy task and prioritization is therefore an area of great interest for policymakers. Too low public vaccine confidence, which results in insufficient vaccine uptake, remains an area of concern for EU policy-makers. Within the European Joint action on vaccination, a work-package dedicated to research aims to define tools and methods for priority-setting in the field of vaccination research. We therefore propose a prioritization framework to identify research priorities towards generating and synthesizing evidence to support policies and strategies aiming at increasing vaccine coverage. Materials/methods We used a multi-criteria decision analysis (MCDA) method inspired by the Child Health and Nutrition Research Initiative developed by Rudan et al. This quantitative methodology follows a series of steps involving different groups of experts and relevant stakeholders. The first step consists in identifying key research questions through a broad consultation. In parallel, a first group of experts is tasked to select criteria for prioritization of research questions, taking into consideration the ultimate goal of the exercise. Another group of experts is then requested to assess a weight to each of the criteria, using pair-wise comparisons. The final step consists in gathering experts who will assess each research question against the weighted criteria. This evaluation leads to assigning a score to each individual research question, which can then be ranked in order of priority. Results We focused our work on four pre-selected pilot vaccines (pertussis, measles containing combination vaccines, influenza and HPV). The consultation generated 124 questions, which were secondarily sorted and re-worded to obtain 27 questions to be ranked. Criteria for setting priorities were the following: accessibility, answerability, deliverability, disease prevalence/incidence, effectiveness, equity, generalization, and territory. During a final face-to-face meeting international experts ranked the 27 questions and agreed on a consensual list of six top-priorities. Conclusions We have developed a transparent, evidence-based rigorous framework to defined key research questions to generate evidence towards the design of policies and strategies to increase vaccine coverage. Results were disseminated broadly and submitted to the EC for potential funding in the context of The Horizon Europe Program. The same process will be conducted in 2021 to identify vaccination research priorities regarding all vaccines used in the EU as well as COVID-19 vaccines.

Immune response induced by COVID-19 vaccine booster against delta and omicron variants was assessed in 65 adults (65–84 years old) early aftesr a first booster dose. An increase in SARS-CoV-2 neutralizing antibodies was shown in individuals not previously infected without evidence of an age-related effect, with lower increase in those infected before a single dose of primary vaccination. Of note, humoral response was observed only starting from the 5th day after the boost.

Sensing of incoming viruses represents one of the pivotal tasks of dendritic cells (DC). Human primary blood DC encompass various subsets that are diverse in their susceptibility and response to HIV-1. The recent identification of Axl+DC, a new blood DC subset, endowed with unique capacities to bind, replicate, and transmit HIV-1 prompted us to evaluate its anti-viral response. We show that HIV-1 induced two main broad and intense transcriptional programs in different Axl+DC potentially induced by different sensors; a NF-κB-mediated program that led to DC maturation and efficient antigen-specific CD4+T cell activation, and a program mediated by STAT1/2 that activated type I IFN and an ISG response. These responses were absent from cDC2 exposed to HIV-1 except when viral replication occurred. Finally, Axl+DC actively replicating HIV-1 identified by quantification of viral transcripts exhibited a mixed NF-κB/ISG innate response. Our results suggest that the route of HIV-1 entry may dictate different innate sensing pathway by DC.

Noninfectious manifestations-allergy, autoimmunity/inflammation, lymphoproliferation, and malignancies-are known to exist in many primary immunodeficiency diseases (PID) and to participate in prognosis.To obtain a global view on their occurrence, we retrieved data from a retrospective cohort of 1375 patients included in the French National Reference Center for Primary Immune Deficiencies (CEREDIH) for whom we had a 10-year follow-up since inclusion in the registry.These patients were followed for 10 years (2009-2018) by specialized centers in university hospitals. This study showed that 20.1% of patients without prior curative therapy (n = 1163) developed at least 1 manifestation (event) encompassing 277 events.Autoimmune/inflammatory events (n = 138) and malignancies (n = 85) affected all age classes and virtually all PID diagnostic groups. They were associated with a risk of death that occurred in 195 patients (14.2%) and were found to be causal in 43% of cases. Malignancies (odds ratio, 5.62; 95% confidence interval, 3.66-8.62) and autoimmunity (odds ratio, 1.9; 95% confidence interval, 1.27-2.84) were clearly identified as risk factors for lethality. Patients who underwent curative therapy (mostly allogeneic hematopoietic stem cell transplantation, with a few cases of gene therapy or thymus transplantation) before the 10-year study period (n = 212) had comparatively reduced but still detectable clinical manifestations (n = 16) leading to death in 9.4% of them.This study points to the frequency and severity of noninfectious manifestations in various PID groups across all age groups. These results warrant further prospective analysis to better assess their consequences and to adapt therapy, notably indication of curative therapy.

Vaccination represents one of the major advances in the field of health. The first vaccines were produced on a rather empirical concept based on the so-called 3I strategy: isolation, inactivation, injection. More recently, protein vaccines have emerged. However, the emergence of new pathogens, the inefficiency of these vaccine strategies to protect against several infections, the need to be able to develop new vaccines quickly and at low cost have led to the development of new types of vaccines. In this context vaccines based on the use of the nucleic acid coding sequences of the antigens of interest (viral vectors, DNA vaccines, RNA vaccines) have been developed in order to improve the efficiency of the currently available vaccines and to propose generic platforms potentially usable against a large number of different pathogens. In addition to the use of these new vaccines, ongoing vaccine research is benefiting from technological developments aimed at optimally delivering vaccines, targeting, for example, dendritic cells, and better characterizing the antigens of interest through the use of vaccines of reverse vaccinology.

Background We investigated the association between socioclinical, inflammatory, and metabolic markers and weight gain in people with human immunodeficiency virus (HIV) on combination antiretroviral therapy (cART). Methods Individuals from the COPANA cohort of normal weight (body mass index [BMI], 18.5–24.9 [ calculated as weight in kilograms divided by height in meters squared) at cART initiation who achieved virological suppression (viral load, Results After 36 months of cART, 32 of 158 people with HIV (20%) became overweight or obese (21% female; 65% born in France and 23% born in sub-Saharan Africa; median BMI at cART initiation, 22 [interquartile range, 21–23]). After adjustment, higher BMI, originating from sub-Saharan Africa, living in a couple, and higher soluble tumor necrosis factor receptor 2 and lower adiponectin concentrations at cART initiation were associated with becoming overweight or obese. Conclusion Weight gain on cART is multifactorial. Special attention should be given to migrants from sub-Saharan Africa. Monocyte activation and adipocyte dysfunction at cART initiation affect weight regulation.

Background Data on the risk factors and outcome of intra-abdominal fungal infections (IAFI) following simultaneous pancreas-kidney transplantation (PKT) are scarce. Materials/methods A retrospective monocentric study was conducted on all patients who underwent simultaneous PKT from January 2007 to December 2016. Deep sites positive cultures for fungi during the first post-transplantation year were collected. Clinical, radiological, and microbiological data of proven and probable invasive fungal infections were analysed. Results Among sixteen PKT patients, 15 were included. Seven patients (47%) developed an invasive fungal infection, exclusively IAFI (six proven, one probable). The proven IAFI included four peritonitis, one pancreatic necrosis with infected hematoma, and one patient with positive preservation fluid only (PF). Candida albicans (n = 4) was the most prevalent species (associated with Galactomyces candidus in one case), C glabrata, C dubliniensis, and C krusei were found in one case each. Three patients had either a positive direct examination and/or culture for renal or pancreatic PF and the culture of PF was positive for the same species that caused IAFI. IAFIs were significantly associated with pancreatic graft arterial thrombosis (5/7 vs 0/8, P = .007) and fungal contamination of PF (3/7 vs 0/8, P = .008). Among patients with IAFI, all required an early surgical revision post-transplantation [1-18 days] and six had early or delayed pancreatic graft removal. One patient died in the first post-transplant year. Conclusion IAFI is a common complication in PKT, associated with pancreatic graft thrombosis or fungal contamination of the graft PF, and can sometimes lead to pancreatic detransplantation.

Achieving a HIV cure has become a research priority. As any improvement of knowledge, which could help scientists design new HIV cure-related clinical trials (HCRCT) depends on the risks potential participants are willing to accept, it is important to understand who will agree or refuse to participate and in which proportions. By providing insights into factors associated with reluctance toward HCRCT participation, our results may help clinicians in patient recruitment.

Background In a context of the evolution of severe morbidities in patients living with HIV (PLWH), the aim of this study was to describe reasons for hospitalization and the mode of care for the patients requiring hospitalization. Methods All admissions (≥ 24 h) of PLWH to 10 hospitals in the south of Paris (COREVIH Ile-de-France Sud) between 1/1/2011 and 12/31/2011 were identified. The hospital database and the file of patients followed in the HIV referral department of each hospital were matched. Detailed clinical and biological data were collected, by returning to the individual medical records, for a random sample (65% of hospitalized patients). Results A total of 3013 hospitalizations (1489 patients) were recorded in 2011. The estimated rate of hospitalized patients was about 8% among the 10105 PLWH routinely managed in COREVIH Ile-de-France Sud in 2011. The majority (58.5%) of these hospitalizations occurred in a unit other than the HIV referral unit. Non-AIDS-defining infections were the main reason for admission (16.4%), followed by HIV-related diseases (15.6%), hepatic/gastrointestinal diseases (12.0%), and cardiovascular diseases (10.3%). The median length of stay was 5 days overall (IQR: 2-11), it was longer among patients admitted to a referral HIV care unit than to another ward. HIV infection had been diagnosed > 10 years previously in 61.4% of these hospitalized patients. They often had associated comorbidities (coinfection HCV/HVB 40.5%, smoking 45.8%; hypertension 33.4%, dyslipidemia 28.8%, diabetes 14.8%). Subjects over 60 years old accounted for 15% of hospitalized patients, most of them were virologically controlled under HIV treatment, and cardiovascular diseases were their leading reason for admission. Conclusion Needs for hospitalization among PLWH remain important, with a wide variety in causes of admission, involving all hospital departments. It is essential to prevent comorbidities to reduce these hospitalizations, and to maintain a link between the management of PLWH, that becomes rightly, increasing ambulatory, and recourse to specialized inpatient services.

Development of a safe, effective and globally affordable Human Immunodeficiency Virus strain 1 (HIV-1) vaccine offers the best hope for future control of the HIV-1 pandemic. However, with the exception of the recent RV144 trial, which elicited a modest level of protection against infection, no vaccine candidate has shown efficacy in preventing HIV-1 infection or in controlling virus replication in humans. There is also a great need for a successful immunotherapeutic vaccine since combination antiretroviral therapy (cART) does not eliminate the reservoir of HIV-infected cells. But to date, no vaccine candidate has proven to significantly alter the natural history of an individual with HIV-1 infection. Areas covered: For over 25 years, the ANRS (France Recherche NordSud Sida-HIV hépatites) has been committed to an original program combining basic science and clinical research developing an epitope-based vaccine strategy to induce a multiepitopic cellular response against HIV-1. This review describes the evolution of concepts, based on strategies using HIV-1 lipopeptides towards the use of dendritic cell (DC) manipulation. Expert commentary: Understanding the crucial role of DCs in immune responses allowed moving from the non-specific administration of HIV-1 sequences with lipopeptides to DC-based vaccines. These DC-targeting strategies should improve HIV-1 vaccine efficacy.

Identification and characterization of CD8+ and CD4+ T-cell epitopes elicited by HIV therapeutic vaccination is key for elucidating the nature of protective cellular responses and mechanism of the immune evasion of HIV. Here, we report the characterization of HIV-specific T-cell responses in cART (combination antiretroviral therapy) treated HIV-1 infected patients after vaccination with ex vivo-generated IFNα Dendritic Cells (DCs) loaded with LIPO-5 (HIV-1 Nef 66–97, Nef 116–145, Gag 17–35, Gag 253–284 and Pol 325–355 lipopeptides). Vaccination induced and/or expanded HIV-specific CD8+ T cells producing IFNγ, perforin, granzyme A and granzyme B, and also CD4+ T cells secreting IFNγ, IL-2 and IL-13. These responses were directed against dominant and subdominant epitopes representing all vaccine regions; Gag, Pol and Nef. Interestingly, IL-2 and IL-13 produced by CD4+ T cells were negatively correlated with the peak of viral replication following analytic treatment interruption (ATI). Epitope mapping confirmed that vaccination elicited responses against predicted T-cell epitopes, but also allowed to identify a set of 8 new HIV-1 HLA-DR-restricted CD4+ T-cell epitopes. These results may help to better design future DC therapeutic vaccines and underscore the role of vaccine-elicited CD4+ T-cell responses to achieve control of HIV replication., Author summary Improvement of therapeutic vaccine strategies in the perspective of HIV cure is warranted and one of the determinant factors for elucidating the nature of protective cellular responses is the identification and characterization of CD8+ and CD4+ T-cell epitopes elicited by the vaccine. However, fine characterization of vaccine response at the level of individual peptides contained in therapeutic vaccines is lacking. Here, we report in-depth characterization of HIV-specific T-cell responses observed in antiretroviral therapy treated HIV-1 infected patients after vaccination with autologous ex vivo-generated IFNα DCs loaded with 5 long HIV peptides coupled to a lipid tail. Our study shows that dominant and subdominant epitopes from Gag, Pol, and Nef vaccine regions are targeted by HIV-specific CD8+ T and CD4+ T cells and that vaccine-elicited HIV-specific CD4+ T cells producing IL-2 and IL-13 are significantly correlated with a better viral control following treatment interruption. These results underscore the role of vaccine-elicited CD4+ T-cell responses to achieve control of HIV replication and thus may inform the design of better therapeutic vaccines.

We previously reported the presence of memory CD4+ T cells that express low levels of SAMHD1 (SAMHD1low) in peripheral blood and lymph nodes from both HIV-1 infected and uninfected individuals. These cells are enriched in Th17 and Tfh subsets, two populations known to be preferentially targeted by HIV-1. Here we investigated whether SAMHD1low CD4+ T-cells harbour replication-competent virus and compartimentalized HIV-1 genomes. We sorted memory CD4+CD45RO+SAMHD1low, CD4+CD45RO+SAMHD1+ and naive CD4+CD45RO-SAMHD1+ cells from HIV-1-infected patients on anti-retroviral therapy (c-ART) and performed HIV-1 DNA quantification, ultra-deep-sequencing of partial env (C2/V3) sequences and phenotypic characterization of the cells. We show that SAMHD1low cells include novel Th17 CCR6+ subsets that lack CXCR3 and CCR4 (CCR6+DN). There is a decrease of the % of Th17 in SAMHD1low compartment in infected compared to uninfected individuals (41% vs 55%, p, Author summary In our previous results we reported that memory CD4+ T cells expressing low levels of SAMHD1 (SAMHD1low) are present in peripheral blood and lymph nodes from HIV-1 infected and uninfected individuals. These cells were enriched in Th17 and Tfh, two populations targeted by HIV-1. Here we used purified memory CD4+CD45RO+SAMHD1low, CD4+CD45RO+SAMHD1+ and naive CD4+CD45RO-SAMHD1+ cells from HIV-1-infected and treated patients to perform cell-associated HIV-1 DNA quantification, p24-producing cells detection, ultra-deep-sequencing of partial env (C2/V3) HIV-1 DNA and further phenotypic characterization. Our results demonstrate that (i) Th17 and CCR6+DN-expressing transcriptional signature of early Th17, two major populations that are susceptible to HIV-1 infection, are present in SAMHD1low cells, and while the former decreased significantly in c-ART HIV-1 infected compared to uninfected individuals, the latter significantly increased; (ii) memory SAMHD1low cells from c-ART patients carry high levels of HIV-1 DNA compared to SAMHD1+ cells, and these levels positively and significantly correlated with Ki67 expression; (iii) memory SAMHD1low cells from patients harbour p24-producing cells; (iv) phylogenetic analyses revealed well-segregated HIV-1 DNA populations with significant compartmentalization between SAMHD1low and SAMHD1+ cells and limited viral exchange. Our data demonstrate that memory SAMHD1low cells contribute to HIV-1 persistence.

Introduction La bronchopneumopathie chronique obstructive (BPCO) represente la 3e cause de deces dans le monde. L’exacerbation aigue est la principale cause de morbi-mortalite. Elle est principalement d’origine infectieuse, impliquant en premier lieu le virus de la grippe. D’autres pathogenes comme Bordetella pertussis (BP) peuvent etre responsables de complications severes. Si la vaccination constitue un element determinant pour proteger le patient BPCO contre ces episodes infectieux, une moins bonne reponse a la vaccination antigrippale a ete observee chez les patients BPCO. L’objectif de notre etude etait d’analyser les reponses humorale et cellulaire apres vaccination anti-BP chez les patients BPCO ce qui a notre connaissance n’a jamais ete realisee. Materiels et methodes Une etude prospective interventionnelle monocentrique a ete mise en place afin d’analyser la reponse immunitaire post-vaccinale specifique contre BP apres une injection de rappel du vaccin tetravalent dTCaPolio (Repevax°). Les parametres etudies ont ete : – j0 : analyse des populations lymphocytaires Tfh, T regulatrices, lymphocytes B naifs et memoires et des anticorps anti-BP ; – j7 post-vaccination (PV) : analyse des populations de plasmablastes et Tfh ; – j15 PV : analyse de la reponse T (restimulation ex vivo avec pool de peptide comprenant FHA, PRN, PT, et Fim 2/3, marquage intracellulaire des cytokines [IL2, IFNg, TNFa]) ; – j30 PV dosage des anticorps anti-BP. Resultats Entre septembre 2018 et mai 2019, 23 patients ont ete inclus : 14 patients BPCO (VEMS/CV : 0,5 ± 0,14) et 9 temoins fumeurs non BPCO apparies sur l’âge et le sexe. A j0, une frequence plus elevee de lymphocytes T CD4+ exprimant PD1 a ete observee chez les patients BPCO (mediane 45,1 % [IQR : 33–55] versus 32,95 % [IQR : 28–40] chez les temoins [p = 0,0241]). On notait une augmentation significative des lymphocytes Tfh et des plasmablastes chez les patients BPCO 7 jours PV (mediane 1,5 %) (IQR : 0,5–2,4) a j0 et 5,2 % (IQR : 1,9–7,5) a j7 (p = 0,002) ; 0,41 % (IQR : 0,2–1,4) a j0 et 2,1 % (IQR : 1,1–5,9) a j7 (p = 0,0039), respectivement, sans difference avec le groupe temoin. A j15 PV, la frequence de LT CD4+ BP specifiques etait de 0,08 % (IQR : 0,06–0,45) chez les sujets temoins et de 0,15 % (IQR : 0,09–0,36) (somme de la production des 3 cytokines IL2, IFNg, TNFa) chez les patients BPCO sans difference significative entre les 2 groupes. A j0, la majorite des sujets presentait un taux faible d’IgG anti-BP. Une augmentation significative de ces anticorps etait observee a j30 (34,5 UI/mL IQR [20,75–139,5] [p = 0,03] vs 39 UI/mL IQR [31–53] [p = 0,002]), pour les groupes temoin et BPCO respectivement, sans difference significative entre les deux groupes. Conclusion Contrairement a ce qui a pu etre observe avec d’autres vaccins, et malgre l’augmentation de PD1 (marqueur d’immunosenescence) sur les lymphocytes T CD4, la reponse vaccinale anti-coquelucheuse tant cellulaire qu’humorale semble conservee chez les sujets avec BPCO, soulignant la pertinence de la revaccination dans cette population vulnerable.

Introduction Une anomalie du follicule pileux serait impliquee dans l’hidradenite suppuree (HS). Nous avons etudie les cellules de la gaine externe du follicule pileux (ORS). Nos resultats montrent que les ORS des patients HS (ORS-HS) secretent spontanement IP-10 et RANTES qui recrutent les cellules immunitaires. Notre etude actuelle se focalise sur la caracterisation des mecanismes a l’origine du profil pro-inflammatoire des ORS-HS. Materiel et methodes Trente-trois patients HS (moyenne d’âge 30,4 ans ; IMC 27,1 ; % femmes : 54 % ; % Fumeurs : 36.3 %) et 25 donneurs sains (moyenne d’âge 34,5 ans ; % femmes : 84 %) sont inclus dans le cadre d’un CPP approuve par le comite d’ethique d’Henri Mondor. Les cellules de l’ORS sont isolees a partir de dechets operatoires de peau apres dissection des follicules pileux. L’expression des ARNm et des proteines sont etudiees par RT-qPCR et Western Blot. L’etude du cycle cellulaire et du phenotype du follicule pileux est realisee par cytometrie en flux. La presence d’ADNsb, de phospho-CHK1 est analysee par immunofluorescence. La vitesse de la fourche de replication est etudiee par la technique du peignage moleculaire. Resultats L’analyse transcriptomique revele une deregulation de l’expression de genes impliques dans le cycle cellulaire et la proliferation des ORS-HS ainsi qu’une signature interferon de type I. L’analyse phenotypique des cellules du follicule pileux montre un enrichissement significatif des cellules progenitrices proliferantes et une perte de la population de cellules souches quiescentes dans les follicules pileux des patients HS. L’etude du cycle cellulaire et de la vitesse de la fourche de replication de l’ADN montrent respectivement une accumulation d’ORS-HS en phase S et un stress replicatif de ces cellules. Ce stress est associe a l’activation de voies de dommages a l’ADN se traduisant notamment par la phosphorylation de CHK1 in vitro dans les ORS-HS et dans les cellules souches fraichement isolees du follicule pileux HS. L’activation des voies de dommages a l’ADN peut conduire a la formation de micronuclei et a l’accumulation d’ADN simple brin cytosolique que nous avons mis en evidence dans les ORS-HS. Nous avons observe que l’accumulation de cet ADN cytosolique active la voie IFI16-STING et entraine la production d’IFN de type I et de leurs genes cibles dans les ORS-HS. Discussion Nos resultats suggerent qu’un defaut de l’homeostasie des cellules souches du follicule pileux serait le primum movens de la maladie et initierait une boucle inflammatoire. Ce defaut fait le lien entre la susceptibilite genetique et l’inflammation chronique observee dans l’HS. Conclusion La mise en evidence de ce nouveau mecanisme dans la physiopathologie de l’HS permet d’envisager de nouvelles cibles therapeutiques.

International audience; Essential HIV cure-related clinical trials (HCRCT) have a potentially high-risk profile in terms of participants' health, which could hinder enrollment by people living with HIV (PLWH) and healthcare professionals (HP). The ANRS-APSEC survey is part of the IAS "Towards an HIV cure" initiative, which promotes multidisciplinary research for a safe, affordable and scalable cure. The study objectives were to understand the psychosocial mechanisms underlying PLWH and HP viewpoints about future HCRCT. Six focus group discussions (three with PLWH (n = 21) and three with HP (n = 30)) were held in three French infectious disease units. From these, three perspectives on HCRCT were identified. The first involved beliefs and knowledge associating HCRCT with poorer health and quality of life for PLWH. The second concerned perceptions of HCRCT as a biological and epidemiological flashback to a situation when HIV infection was left uncontrolled. The third was characterized by aspects of historical HIV culture that embrace innovation.

Introduction Dans le developpement clinique vaccinal, l’evaluation de la capacite du vaccin candidat a generer des reponses immunitaires est un objectif important. La mesure de l’immunogenicite cellulaire s’effectue en cytometrie de flux multiparametrique permettant la caracterisation de lymphocytes T produisant des cytokines apres stimulation antigenique specifique. L’approche statistique actuellement utilisee pour l’analyse de ces donnees consiste a effectuer une comparaison inter-bras ou intra-bras des pourcentages de cellules produisant une ou des cytokine(s) d’interet, apres soustraction de la reponse observee dans des cellules non-stimulees (NS) de chaque echantillon. Soustraire cette reponse NS vise a analyser la reponse specifique a l’antigene, mais souleve des questions methodologiques liees a l’erreur de mesure, a des biais potentiels et a la puissance statistique. Un modele bivarie modelisant simultanement la reponse NS et la reponse induite par la stimulation specifique (S) permet une evaluation plus valide de l’effet du vaccin dans les essais cliniques vaccinaux. Methodes Nous avons construit un modele lineaire bivarie modelisant simultanement un vecteur de reponse avec deux variables dependantes (reponses NS et S) et l’effet du vaccin comme principale variable explicative. Les performances du modele ont ete evaluees au travers de simulations numeriques avec differents scenarii en termes de biais et de controle des erreurs de type 1 et 2, en comparaison des approches conventionnelles. Nous avons applique ce modele sur les donnees de deux essais vaccinaux contre le VIH (ANRS VRI01 et VRI02 ANRS 149 LIGHT). Les simulations ont ete effectuees sous SAS ; l’implementation du modele sous SAS (proc mixed) et R (package nlme). Resultats Cette nouvelle methode permet de modeliser une relation lineaire entre la reponse NS et les reponses antigeniques, tout en tenant compte de la correlation dans leur erreur de mesure. Le modele garantit un controle de l’erreur de type 1 en toute circonstances et une puissance statistique toujours au moins aussi bonne que l’approche conventionnelle dans tous les scenarii ( Fig. 1 ). Le modele a aussi ete applique sur les essais ANRS VRI01 et VRI02 ANRS 149 LIGHT. Conclusion Cette nouvelle methode permet de prendre en compte toutes les informations disponibles contrairement aux approches conventionnelles, conduisant a des resultats plus robustes et une absence de biais dans l’evaluation de l’immunogenicite vaccinale.

Summary The virological diagnosis of Parvovirus B19 (PvB19) infection is currently based on sero-diagnosis, molecular methods or both, yet without clear recommendations. We retrospectively identified patients with polymerase chain reaction-positive PvB19 and/or positive serological assay between 2007 and 2013. Eighty-two adults with at least one diagnostic criterion of recent PvB19 infection (IgM antibodies, viral DNA in blood and/or in marrow) were included and classified into three homogeneous groups: 30 patients had no underlying predisposing condition, 25 a hereditary haemolytic anaemia, 27 an underlying immunodeficiency. The classical PvB19related manifestations were less frequent in immunocompromised than in immunocompetent patients (arthromyalgia: 5 vs. 14; erythema: 4 vs. 17, respectively). Only 414% of patients with no underlying disease were anaemic. Bicytopenia and pancytopenia were observed mainly in immunocompromised patients. Classical pure red cell aplasia was observed in only 9 of the 27 marrow smears performed. Specific IgM were found in 93% of immunocompetent patients, whereas only 58% had detectable viral DNA in blood. IgM and DNA were present alone or together in all patients with hereditary haemolytic anaemia. In immunocompromised patients, the diagnosis was confirmed by marrow analysis in 91% of cases. We make some proposals based on this large series of PvB19-infected patients.

Background HIV treatment for individuals with end-stage renal disease (ESRD) on hemodialysis (HD) has previously required complex dose-adjusted regimens. We evaluated the safety and efficacy of single-tablet, once-daily elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide (E/C/F/TAF) in people living with HIV (PLH) and ESRD on chronic HD. Methods Virologically suppressed adult PLH with ESRD on chronic HD for ≥ 6 months were switched to open-label E/C/F/TAF 150/150/200/10 mg once daily for 96 weeks. Efficacy was assessed as the proportion of participants who maintained virologic suppression (HIV RNA < 50 copies/mL) using the snapshot algorithm. Safety and participant satisfaction were assessed throughout the study. Results We enrolled 55 participants with median age 51 years (range 23–64) with median time on HD 6 years (range 1–17). In the per protocol analysis set, virologic suppression was maintained in 30 of 31 participants (96.8%, 95% CI [83.3%, 99.9%]) at week 96. In the full analysis set, virologic suppression was maintained in 30 of 55 participants (54.5%; 95% CI [40.6%, 68.0%]); one discontinued therapy due to lack of efficacy, and W96 data were unavailable for 24. Of the 24 participants lacking W96 data, 17 discontinued study drug early and 7 had missing data while on study drug; all had HIV RNA < 50 copies/mL at the last pre-week 96 check. Treatment-emergent AEs occurred in 53 (96.4%) participants, and study-drug-related AEs occurred in 7 (12.7%). Treatment-emergent AEs leading to premature study drug discontinuation occurred in 4 (7.3%) participants; two were considered study-drug-related (allergic pruritus and peripheral neuropathy in one participant each). No study-drug-related serious AEs were observed. 85.7% (30/35) of responding participants reported they were ‘much more satisfied’ with their regimen. Conclusion Single-tablet, once-daily E/C/F/TAF was effective in maintaining virologic suppression in PLH on chronic HD over 96 weeks of follow-up. E/C/F/TAF was well tolerated and was associated with improved participant satisfaction. These data demonstrate that E/C/F/TAF is a safe and effective alternative to more complicated regimens in PLH on chronic HD, with the potential to improve patient satisfaction and quality of life. Disclosures All authors: No reported disclosures.

Introduction La physiopathologie de l’hidradenite suppuree (HS) est mal comprise. Les cellules dendritiques (DC), a l’interface entre l’immunite innee et adaptative, pourraient faire le lien entre l’environnement notamment bacterien de la flore commensale et le recrutement chronique de lymphocytes T. La caracterisation des sous-populations de DC n’a jamais ete faite dans cette pathologie. Nous avons caracterise les DC cutanees et circulantes de HS en comparant a des temoins (HD). Materiel et methodes L’etude reposait sur un CCP avec consentement ecrit des patients. Tous les patients HS inclus (n = 5 peau, n = 10 sang) ne prenaient aucun traitement immunomodulateur et presentaient des stades Hurley et phenotypes LC differents. Les sous-types de DC marquees par differents panels d’anticorps etaient analyses au cytometre en flux. Etaient caracterisees dans la peau, les cellules de Langherans (LC), les DC epidermiques (eDC), les DC dermiques (dDC), les DC plasmacytoides (pDC), et dans le sang les pDC et les DC issues de monocytes (mDC) CD1c+ et CD141+. L’analyse statistique etait faite par Mann-Whitney U test. Resultats Dans la peau, la frequence de pDC etait significativement augmentee dans l’epiderme HS compare au HD (7,03 % vs 0,22 %, p = 0,004). A l’inverse, les LC et dDC etaient diminuees (respectivement, moyenne : 22,23 % versus 83 %, p = 0,003 et 4,21 % vs 65,44 %, p = 0,03). La frequence des eDC n’etait pas differente (3,18 % vs 1,54 %, p = 0,23). Dans le sang, la frequence des pDC etait significativement diminuee chez les HS (moyenne : 0,18 % vs 0,60 %, p = 0,009). Les mDC CD1c+ et mDC CD141+ etaient egalement diminuees chez les HS (respectivement, moyenne 0,27 % vs 0,49 % p = 0,043, et 0,06 % vs 0,19 %, p = 0,042). Au total, la frequence des pDC dans l’epiderme etait significativement augmentee chez les HS et diminuee dans leur sang ( Fig. 1 et 2 ). Discussion Nous retrouvons un infiltrat cutane de pDC probablement recrutees a partir du sang. En effet, les resultats du laboratoire montrent une secretion spontanee d’IP-10 et RANTES par les ORS, cellules souches du follicule pileux, des patients HS. Ces chemokines pourraient etre a l’origine du recrutement des pDC. Ces pDC activees par les produits microbiens secreteraient de l’IFN type 1 entrainant un environnement pro-inflammatoire. Celui-ci accentuerait l’activation des ORS creant ainsi un cercle vicieux a l’origine de l’inflammation chronique observee dans l’HS. Conclusion L’infiltration significative de pDC dans la peau pourrait etre au centre de la physiopathologie de l’HS par l’installation d’un environnement IFN type 1. Compte tenu de l’absence d’efficacite a long terme des traitements utilises en pratique courante, nous pourrions envisager a terme des traitements ciblant la voie de l’IFN type 1 dans l’HS.

International audience; OBJECTIVE: To dissect the biological mechanisms involved in the cellular responses to a candidate vaccine containing 5 HIV peptides coupled to a palmytoil tail (HIV-LIPO-5) in healthy volunteers, by using extensive immunogenicity assessments with different stimulation durations. DESIGN: Immunogenicity substudy of a randomized phase II prophylactic HIV vaccine trial (ANRS VAC 18). METHODS: HIV-LIPO-5 or placebo was administered at W0, W4, W12 and W24. Peripheral blood mononuclear cells from a subset of participants at W0 and W14 were stimulated with HIV-LIPO-5, Gag peptides contained in the vaccine and control peptides. ELISpot, lymphoproliferation, intracellular cytokine staining (ICS), cytokine multiplex and transcriptomic analyses were performed. Different time points and stimulation conditions were compared, controlling for test multiplicity. RESULTS: Cultured ELISpot and lymphoproliferation responses were detected at W14. Ex-vivo ICS showed mainly interleukin (IL)-2-producing cells. Secretion of interferon (IFN)-γ, tumour necrosis factor (TNF)-α, IL-5 and IL-13 increased significantly after culture and Gag stimulation at W14 compared to W0. Metallothionein genes were consistently overexpressed after HIV-LIPO-5 stimulation at W0 and W14. At W14, significant probes increased substantially, including IFN-γ, CXCL9, IL2RA, TNFAIP6, CCL3L1 and IL-6. Canonical pathway analyses indicated a role of interferon signalling genes in response to HIV-LIPO-5. CONCLUSION: HIV-LIPO-5 vaccination elicited Th1 and Th2 memory precursor responses and a consistent modulation in gene expression. The response profile before vaccination suggests an adjuvant effect of the lipid tail of HIV-LIPO-5. Our combined immunogenicity analyses allowed to identify a specific signature profile of HIV-LIPO-5 and indicate that HIV-LIPO-5 could be further developed as a prime in heterologous prime-boost strategies.

International audience; Evidence before this study We searched PubMed on June 30, 2016, for English-language cohort studies published since Jan 1, 1980, of patients with invasive listeriosis worldwide with the keywords " listeria " , " listeriosis " , " maternal " , and " neurolisteriosis ". Studies had to include epidemiological or clinical data on listeriosis. All clinical forms of infection were included (bacteraemia, neurolisteriosis, and maternal–neonatal infection). Host risk factors for listeriosis have been well identified, but the clinical features and prognostic factors of the disease are based on retrospective studies compiling heterogeneous data or random collected cases. Furthermore, no clinical trial has ever been done and medical management is not evidence based. Added value of the study Our study is the first prospective clinical study focusing on all forms of invasive listeriosis. The study is based on a national mandatory system that allowed the nearly complete capture of microbiologically proven cases. The study shows a higher burden of listeriosis than reported before: more than 80% of infected mothers experienced major fetal or neonatal complications (fetal loss, very high prematurity, early or late onset disease); only 39% of patients with neurolisteriosis survived and fully recovered. The study provides important new data to improve management and predict outcome in listeriosis, such as determination of the time window for fetal losses (

The quest for an effective HIV-1 vaccine began early in the course of the HIV pandemic. Over time, the paradigm has evolved from B cell- towards T cell-based vaccines. Results from initial Phase II/III trials have been disappointing; however, while modest, the unexpected results of the Phase II/III RV144 trial in Thailand have re-energised the field. Indeed a clear correlation was demonstrated in this trial between protection and immunological biomarkers, namely non-neutralising antibodies against the V1V2 region. Recent data obtained from cohorts of recently HIV-1-infected individuals have enabled exploration of the role of neutralising antibodies and their potential use in HIV-1 prevention. Results from non-human primate models using a cytomegalovirus vector have also shown the potential for a prophylactic HIV vaccine to induce effective T cell responses. Finally, the development of new vaccine vectors and trial strategies has also allowed progress in the field. Therefore, HIV-1 vaccine research remains a dynamic field that has also been stimulated by the recent positive results of pre-exposure prophylaxis strategies with antiretrovirals.

Supplemental Digital Content is available in the text, The impact of the investigational human immunodeficiency virus type 1 (HIV-1) F4/AS01B vaccine on HIV-1 viral load (VL) was evaluated in antiretroviral therapy (ART)-naive HIV-1 infected adults. This phase IIb, observer-blind study (NCT01218113), included ART-naive HIV-1 infected adults aged 18 to 55 years. Participants were randomized to receive 2 (F4/AS01B_2 group, N = 64) or 3 (F4/AS01B_3 group, N = 62) doses of F4/AS01B or placebo (control group, N = 64) at weeks 0, 4, and 28. Efficacy (HIV-1 VL, CD4+ T-cell count, ART initiation, and HIV-related clinical events), safety, and immunogenicity (antibody and T-cell responses) were evaluated during 48 weeks. At week 48, based on a mixed model, no statistically significant difference in HIV-1 VL change from baseline was demonstrated between F4/AS01B_2 and control group (0.073 log10 copies/mL [97.5% confidence interval (CI): −0.088; 0.235]), or F4/AS01B_3 and control group (−0.096 log10 copies/mL [97.5% CI: −0.257; 0.065]). No differences between groups were observed in HIV-1 VL change, CD4+ T-cell count, ART initiation, or HIV-related clinical events at intermediate timepoints. Among F4/AS01B recipients, the most frequent solicited symptoms were pain at injection site (252/300 doses), fatigue (137/300 doses), myalgia (105/300 doses), and headache (90/300 doses). Twelve serious adverse events were reported in 6 participants; 1 was considered vaccine-related (F4/AS01B_2 group: angioedema). F4/AS01B induced polyfunctional F4-specific CD4+ T-cells, but had no significant impact on F4-specific CD8+ T-cell and anti-F4 antibody levels. F4/AS01B had a clinically acceptable safety profile, induced F4-specific CD4+ T-cell responses, but did not reduce HIV-1 VL, impact CD4+ T-cells count, delay ART initiation, or prevent HIV-1 related clinical events.

Activating mutations in NOTCH1, an essential regulator of T cell development, are frequently found in human T cell acute lymphoblastic leukemia (T-ALL). Despite important advances in our understanding of Notch signal transduction, the regulation of Notch functions in the nucleus remains unclear. Using immunoaffinity purification, we identified NOTCH1 nuclear partners in T-ALL cells and showed that, beyond the well-characterized core activation complex (ICN1-CSL-MAML1), NOTCH1 assembles a multifunctional complex containing the transcription coactivator AF4p12, the PBAF nucleosome remodeling complex, and the histone demethylases LSD1 and PHF8 acting through their demethylase activity to promote epigenetic modifications at Notch-target genes. Remarkably, LSD1 functions as a corepressor when associated with CSL-repressor complex and as a NOTCH1 coactivator upon Notch activation. Our work provides new insights into the molecular mechanisms that govern Notch transcriptional activity and represents glimpse into NOTCH1 interaction landscape, which will help in deciphering mechanisms of NOTCH1 functions and regulation.

Interleukin 7 (IL7) is a critical factor for lymphocyte homeostasis. A dysfunction of the IL7/IL7R pathway has previously been described in HIV-1 infection, and promising results were observed in recent analyses of IL7 for therapeutic use in HIV infected individuals. However, further investigations are still warranted to understand the possible roles of this cytokine. Here, we explored whether the IL7 and IL7RA genetic polymorphisms were associated with the progression of HIV infection. We extensively genotyped the IL7 and IL7RA genes in the GRIV (Genomics of Resistance to Immunodeficiency Virus) cohort, composed of patients with extreme progression profiles - long-term non (LTNP) and rapid (RP) progressors--, and in a healthy control group (CTR). Statistical case-control analyses were performed using the Fisher's exact test, comparing either LTNP vs CTR or RP vs CTR. Three IL7RA SNPs (single nucleotide polymorphisms--rs7701176, rs987106 and rs10491434), but no IL7 SNPs, were significantly associated with rapid disease progression (P0.01). In a multi-marker analysis focusing on functional variants, a strong association between an IL7RA haplotype and rapid progression was observed (P = 5.59 x 10(-3)). In summary, our comprehensive genetic study revealed three SNPs and a risk of haplotype associated with rapid progression to AIDS in the IL7RA gene. Interestingly, the haplotype is composed of SNPs previously identified in other inflammatory diseases (e.g., multiple sclerosis) by GWAS and by functional studies. Our results contribute to the growing understanding of the role of IL7/IL7R in HIV disease progression, and more widely, in CD4+ T cell homeostasis.

Introduction La prophylaxie pre-exposition (PrEP) diminue le risque de contamination par le VIH dans les populations a risque. Elle est utilisee, soit en continu, soit a la demande. Une diminution moderee de la clairance de creatinine a ete constatee dans les essais cliniques internationaux (Salomon, AIDS 2014 ; Ghandi, Lancet-HIV 2016), incitant a surveiller la fonction renale de ces patients. Dans notre centre, a partir de juillet 2016, une surveillance renale trimestrielle est effectuee chez les patients traites par TDF-Emtricitabine dans le cadre de la PrEP. Nous presentons ici les resultats de ce suivi. Patients/materiels et methodes Le suivi renal trimestriel comportait l’estimation du DFG a partir de la creatinine et de la cystatine C (formules CKD-EPIcreat et CKD-EPIcys), le depistage de signes de tubulopathie proximale (uricemie et excretion fractionnelle d’acide urique, phosphatemie et TmPi/DFG, cystatinurie), ainsi qu’un dosage de proteinurie et de microalbuminurie. Resultats Cinquante-six patients (55 hommes, 1 femme), âges de 37,3 ± 10,6 ans ont ete traites depuis juillet 2016, (suivi median de 6 mois). Vingt-huit patients on pris le traitement en continu, et 28 a la demande. Dans le groupe traite en continu, CKD-EPIcreat a diminue de 102,9 ± 15,1 a 97,8 ± 13,6 mL/min/1,73 m2 (Δ DFG 5 %) p = 0,03, puis est reste stable ensuite. CKD-EPIcys etait en revanche inchange (103,7 ± 14,7 puis 101,8 ± 15,2 mL/min/1,73 m2 a 3 mois, p = 0,4). Dans le groupe traite a la demande, le DFG estime etait stable pour les 2 marqueurs. Dans les 2 groupes il n’y avait pas de modification des parametres tubulaires, ni de modification de proteinurie et de microalbuminurie. Aucun patient n’a arrete le traitement en raison d’une toxicite renale. Conclusion Chez les patients traites en continu, la diminution du DFG estime a partir de la creatinine, alors que l’estimation a partir de la cystatine C est stable, pose question. La cystatine C, produite par l’ensemble des cellules nucleees de l’organisme et eliminee par filtration glomerulaire. L’excretion renale de creatinine se fait par filtration glomerulaire, mais aussi (20 % en moyenne) par secretion tubulaire. Chez les patients sous PrEP en continu, l’elevation de la creatinine alors que la cystatine C reste stable, suggere que le TDF/Emtricitabine soit responsable d’un blocage partiel de la secretion tubulaire de creatinine. Il pourrait s’agir soit du blocage d’un transporteur, soit d’un effet lesionnel direct sur la cellule tubulaire. Le suivi a long terme de ces patients est necessaire pour determiner si cette anomalie predispose a une authentique toxicite renale.

a Background. The compilation of previous genomewide association studies of AIDS shows a major polymor- phism in the HCP5 gene associated with both control of the viral load and long-term nonprogression (LTNP) to AIDS. Methods. To look for genetic variants that affect LTNP without necessary control of the viral load, we reanalyzed the genomewide data of the unique LTNP Genomics of Resistance to Immunodeficiency Virus (GRIV) cohort by excluding "elite controller" patients, who were controlling the viral load at very low levels (!100 copies/mL). Results. The rs2234358 polymorphism in the CXCR6 gene was the strongest signal ( ; odds ratio, 7 P p 2.5 10 1.85) obtained for the genomewide association study comparing the 186 GRIV LTNPs who were not elite controllers with 697 uninfected control subjects. This association was replicated in 3 additional independent European studies, reaching genomewide significance of . This association with LTNP is independent of the 10 P p 9.7 10 combined CCR2-CCR5 locus and the HCP5 polymorphisms. Conclusions. The statistical significance, the replication, and the magnitude of the association demonstrate that CXCR6 is likely involved in the molecular etiology of AIDS and, in particular, in LTNP, emphasizing the power of extreme-phenotype cohorts. CXCR6 is a chemokine receptor that is known as a minor coreceptor in human immunodeficiency virus type 1 infection but could participate in disease progression through its role as a mediator of inflammation.

BACKGROUND French National Agency for Research on AIDS and Viral Hepatitis's HIV-LIPO-5 vaccine includes five HIV-1 peptides, containing multiple CD8 and CD4 T-cell epitopes and coupled to a palmitoyl tail. Whether HIV-LIPO-5 immunogenicity varies with the dose is unknown. METHODS HIV-negative volunteers were randomized to receive HIV-LIPO-5 vaccine at 50 microg/lipopeptide (N = 32), 150 microg/lipopeptide (N = 32), 500 microg/lipopeptide (N = 33) or placebo (N = 34) at weeks 0, 4, 12 and 24. HIV-1-specific CD8 (interferon-gamma ELISpot on peripheral blood mononuclear cells cultured for 12 days) and CD4 responses (peripheral blood mononuclear cell lymphoproliferation) were assessed at baseline, after each injection and at week 48. RESULTS Local reactions were dose-dependent but no differences in systemic reactions appeared between groups. Sustained (at least on two separate occasions) CD8 response rates to at least one given HIV-1 pool were obtained in 22 of 32 (69%), 21 of 33 (64%) and 21 of 34 (62%) individuals for LIPO-5 50, 150 and 500 groups, respectively (P < or = 0.0001 for all comparisons to the placebo). Cumulative CD4 response rates were obtained in 15 of 32 (47%), 18 of 33 (55%) and 15 of 34 (44%) individuals (P < 0.0001 for all comparisons to placebo). At week 48, CD8 responses persisted in 47 of 91 (52%) HIV-LIPO-5 recipients. CONCLUSION Doses of 50, 150 and 500 microg of French National Agency for Research on AIDS and Viral Hepatitis's HIV-LIPO-5 vaccine were able to elicit HIV-specific sustained CD8 and CD4 T-cell responses in healthy adults. Safety is good and all doses appear appropriate in further 'prime-boost' trials.

Notch and its ligands regulate multiple cell fate decisions. However, several questions on the timing, durability, and reversibility of Notch signaling effects on human hematopoietic precursors are still unresolved. Here, we used recombinant Delta ligands to deliver temporally and dose-controlled signals to human immature cord blood CD34+CD38low cells at clonal cell levels. Notch activation increased the frequency of multipotent progenitors, skewed the T and natural killer (NK) cell potential of CD34+CD38low clones in a dose- and ligand-dependent manner, and inhibited the differentiation of B cell clones. Low doses of ligands were sufficient for significantly increasing the frequency of NK cell precursors, whereas higher doses were required for increasing the frequency of T-cell clones. Interestingly, we demonstrate that temporary Notch activation prevents the subsequent differentiation of CD34+CD38low cells beyond a pro-B CD79a+CD19− stage characterized as a common lymphoid progenitor (CLP). Moreover, the lymphoid potential of this pro-B/CLP was skewed toward NK cell potential while the B cell precursor frequency was dramatically reduced. These results indicate critical timing and quantitative aspects of Notch/Delta interactions, imprinting the potential of CD34+CD38low hematopoietic progenitors. These results may have implications both in physiology and for cell manipulation because they demonstrate a tight regulation of the fate of human progenitors by Notch signaling. STEM CELLS 2009;27:1676–1685 Disclosure of potential conflicts of interest is found at the end of this article.

Angiitis of the central nervous system (CNS) in patients infected with HIV-1-is often associated with concomitant infection or lymphoproliferative disease of the CNS. Four HAART naïve patients infected with HIV-1 with severe stroke are described. Evidence of vasculitis was found by magnetic resonance angiography. Extensive investigations excluded concomitant opportunistic, lymphoproliferative or autoimmune disorders leading to the diagnosis of primary angiitis of the CNS. Despite initiation of HAART and prolonged suppression of viral replication, these patients remained severely immunosuppressed. The addition of corticosteroids led to a significant improvement of clinical symptoms. Primary angiitis of the CNS should be considered in patients with HIV and stroke. The prognosis of these patients remain poor despite HAART. These observations suggest that the vascular inflammatory process persists despite the control of viral load under HAART in patients with persistent immunosuppression.

International audience; OBJECTIVE: Expansion of regulatory T (Treg) cells has been described in chronically HIV-infected individuals. We investigated whether HIV-suppressive Treg could be detected during primary HIV infection (PHI). METHODS: Seventeen patients diagnosed early after PHI (median: 13 days; 1-55) were studied. Median CD4 cell count was 480 cells/microl (33-1306) and plasma HIV RNA levels ranged between 3.3 and 5.7 log10 copies/ml. Suppressive capacity of blood purified CD4CD25 was evaluated in a coculture assay. Fox-p3, IL-2 and IL-10 were quantified by reverse transcriptase (RT)-PCR and intracellular staining of ex vivo and activated CD4+CD25 T cells. RESULTS: The frequency of CD4CD127CD25 T cells among CD4 T cells was lower in patients with PHI compared with chronic patients (n = 19). They exhibited a phenotype of memory T cells and expressed constitutively FoxP3. Similar to chronic patients, Treg from patients with PHI inhibited the proliferation of purified tuberculin (PPD) and HIV p24 activated CD4CD25 T cells. CD4CD25 T cells from patients with PHI responded specifically to p24 stimulation by expressing IL-10. In untreated patients with PHI, the frequency as well as HIV-specific activity of Treg decreased during a 24-month follow-up. A positive correlation between percentages of Treg and both CD4 cell counts and the magnitude of p24-specific suppressive activity at diagnosis of PHI was found. CONCLUSION: Our data showed that HIV drives Treg, as PHI and these cells persist throughout the course of the infection. A correlation between the frequency of Treg and CD4 T-cell counts suggest that these cells may impact on the immune activation set point at PHI diagnosis.

Introduction: PAH onset during HIV infection has an epidemiological pattern which matches with a "non-AIDS event" (i.e.:not linked to HIV-load or T-CD4+ level). Inflammation mediated by monocytes in response to bacterial translocation from the gut is involved in non-AIDS events onset. We conducted a proof of concept study to evaluate the soluble (s)CD14 and (s)CD163 levels, which both increase after monocyte activation by lipopolysaccharide (LPS), and so used as surrogate markers of both bacterial translocation and monocyte activation in non-AIDS events evaluation. Methods: We compared a HIV-PAH group (n=11) to a HIV-infected group without PAH (n=11) to ensure that sCD14 or sCD163 were higher in the HIV-PAH group. Results: Both sCD14 and sCD163 were significantly higher in HIV-PAH group versus HIV-group. Moreover sCD14 significantly decrease in HIV-PAH sub-group with normalized hemodynamics. The same result was obtained for TNF level. PAH-HIV group also experienced a distinct monocyte phenotype pattern (CD163+) and a higher number of activated CD8+T-cells (HLADR+CD38+). As surrogate markers of LPS translocation (LBP) and enterocyte apoptosis (I-FABP) appeared similar between the two groups we looked for a higher LPS-sensitivity of monocytes in HIV-PAH group, which effectively exhibited a higher level of TNF after LPS stimulation in vitro. Conclusion: These preliminaries data are consistent with an association between inflammation and HIV-PAH onset. The inflammation seems related to monocyte activation with LPS translocation and a particular susceptibility of monocytes to LPS in the HIV-PAH group.

Objective The Notch pathway plays a key role in cell fate choices and in T-cell development. The goal of our study was to evaluate whether a short in vitro stimulation of the Notch pathway may alter human progenitor cell behavior. Methods CD34 + cord blood progenitors were exposed for 4 days to either immobilized Notch ligand Delta-4 or in control conditions. Phenotypic and molecular changes induced by the short stimulation were assessed at day 4. Next, long-term alteration of the fate of these progenitors was assessed in culture conditions suitable for B (coculture with MS5 stromal cells) and T (FTOC and OP9 stromal cells expressing Delta-4 systems) cell differentiation. Results Notch activation was sufficient to trigger immunophenotypic and molecular changes consistent with early T-cell lineage differentiation. Delta-4 induced, in 4 days, CD7 + cytCD3ɛ + cells. This paralleled at the gene-transcription level with de novo expression of several T cell–related transcription factors and TCRγ rearrangement, while B cell transcripts were simultaneous silenced. As compared to non-Delta-4 primed cells, these early changes translated to long-term alteration of the potential of cells. Delta-4 priming led to an acceleration of T-cell development, including a completion of the TCR rearrangement, when cells were cultured in systems suitable for T-cell development while B-cell development was inhibited. Conclusion A transient Notch activation is sufficient to promote T-cell differentiation from cord blood CD34 + cells. This system may be a useful tool for the amplification and the quantification of the T potential of CD34 + cells in various disease conditions.

OBJECTIVE. Our objective was to describe the various imaging patterns of Fabry disease, including cerebrovascular, renal, cardiac, and other organ involvement. Fabry disease, an X-linked inborn error of glycosphingolipid catabolism resulting from a deficient activity of the hydrolase α-galactosidase A, displays more complications in men than in heterozygous women.CONCLUSION. It is up to radiologists to evoke the diagnosis, help practitioners in treating patients early with enzyme replacement therapy, and monitor its efficacy.

Fas-mediated T-cell death is known to occur during human immunodeficiency virus (HIV) infection. In this study, we found that HIV type 1 LAI (HIV-1LAI) primes CD8+T cells from healthy donors for apoptosis, which occurs after Fas ligation. This effect is counteracted by a broad caspase inhibitor (zVAD-fmk). Fas-mediated cell death does not depend on CD8+T-cell infection, because it occurred in the presence of reverse transcriptase inhibitors. However, purified CD8+T cells are sensitive to Fas only in the presence of soluble CD4. Finally, we found that interleukin 7 (IL-7) increases Fas-mediated CD4+and CD8+T-cell death induced by HIV-1LAI. Since high levels of IL-7 are a marker of poor prognosis during HIV infection, our data suggest that enhancement of Fas-mediated T-cell death by HIV-1LAIand IL-7 is one of the mechanisms involved in progression to AIDS.

Posttransplant lymphoproliferative disorders are lymphoid proliferations or lymphomas, usually associated with Epstein-Barr virus infection, that develop as the consequence of immunodepression. These disorders usually affect patients receiving high doses of cyclosporine in the context of bone marrow or organ transplantations. Posttransplant lymphoproliferative disorders can regress when cyclosporine is discontinued. Such lymphoproliferations rarely occur for patients receiving low-dose cyclosporine treatments for autoimmune disorders. In the following report, we describe a patient with psoriasis vulgaris treated with long-term low-dose cyclosporine who developed an acute Epstein-Barr virus-associated clonal lymphoproliferative disorder associated with hemophagocytic syndrome. This lymphoproliferative disorder resembling classic posttransplant lymphoproliferative disorder regressed when cyclosporine was discontinued.