Infection of Semen-Producing Organs by SIV during the Acute and Chronic Stages of the Disease

International audienceBACKGROUND: Although indirect evidence suggests the male genital tract as a possible source of persistent HIV shedding in semen during antiretroviral therapy, this phenomenon is poorly understood due to the difficulty of sampling semen-producing organs in HIV+ asymptomatic individuals. METHODOLOGY/PRINCIPAL FINDINGS: Using a range of molecular and cell biological techniques, this study investigates SIV infection within reproductive organs of macaques during the acute and chronic stages of the disease. We demonstrate for the first time the presence of SIV in the testes, epididymides, prostate and seminal vesicles as early as 14 days post-inoculation. This infection persists throughout the chronic stage and positively correlates with blood viremia. The prostate and seminal vesicles appear to be the most efficiently infected reproductive organs, followed by the epididymides and testes. Within the male genital tract, mostly T lymphocytes and a small number of germ cells harbour SIV antigens and RNA. In contrast to the other organs studied, the testis does not display an immune response to the infection. Testosteronemia is transiently increased during the early phase of the infection but spermatogenesis remains unaffected. CONCLUSIONS/SIGNIFICANCE: The present study reveals that SIV infection of the macaque male genital tract is an early event and that semen-producing organs display differential infection levels and immune responses. These results help elucidate the origin of HIV in semen and constitute an essential base to improving the design of antiretroviral therapies to eradicate virus from semen

Cause of Death and Predictors of All-Cause Mortality in Anticoagulated Patients With Nonvalvular Atrial Fibrillation : Data From ROCKET AF

M. Kaste on työryhmän ROCKET AF Steering Comm jäsen.Background-Atrial fibrillation is associated with higher mortality. Identification of causes of death and contemporary risk factors for all-cause mortality may guide interventions. Methods and Results-In the Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET AF) study, patients with nonvalvular atrial fibrillation were randomized to rivaroxaban or dose-adjusted warfarin. Cox proportional hazards regression with backward elimination identified factors at randomization that were independently associated with all-cause mortality in the 14 171 participants in the intention-to-treat population. The median age was 73 years, and the mean CHADS(2) score was 3.5. Over 1.9 years of median follow-up, 1214 (8.6%) patients died. Kaplan-Meier mortality rates were 4.2% at 1 year and 8.9% at 2 years. The majority of classified deaths (1081) were cardiovascular (72%), whereas only 6% were nonhemorrhagic stroke or systemic embolism. No significant difference in all-cause mortality was observed between the rivaroxaban and warfarin arms (P=0.15). Heart failure (hazard ratio 1.51, 95% CI 1.33-1.70, P= 75 years (hazard ratio 1.69, 95% CI 1.51-1.90, P Conclusions-In a large population of patients anticoagulated for nonvalvular atrial fibrillation, approximate to 7 in 10 deaths were cardiovascular, whereasPeer reviewe

MicroRNA-sequencing in a mouse model of peanut sensitized mice treated by EPIT identifies early changes in microRNA expression influencing T-cell plasticity and Th2 cytokine production

International audienceIntroduction:Epicutaneous immunotherapy (EPIT) is a safe treat-ment for food allergy. In animal models, EPIT protection seems toconfer sustained unresponsiveness and prevents further sensitiza-tion. We have previously shown DNA methylation changes in keytranscription factors to be associated with EPIT and sustained unre-sponsiveness.Objectives:This study investigates the kinetics of miRNA expres-sion patterns underlying the therapeutic effect of EPIT and its per-sistence. BALB/c mice were orally sensitized to peanut and thentreated with EPIT or not treated (sham). Mice (n=112) were sacri-ficed during treatment at 1, 2, 4, 6 and 8 weeks; and 8 weeks afterthe end of treatment. MiRNAs were analysed in sorted CD4+cellsfrom spleen using high-throughput sequencing on a HiSeq4000 to adepth of 200M bases / sample and validated by qPCR.Results:Global miRNA profiles consisting of 800-1000 miRNAsreproducibly detected in the CD4 samples distinguished EPIT-treatedmice from controls as early as one week following initiation of treat-ment. Intra-group variability of miRNA expression profiles was muchreduced in the EPIT group at all time points. Between 23 and 190MiRNAs were found to be differentially expressed at padj<.05 with alarge overlap of miRNAs between adjacent time points. Differentiallyexpressed miRNAs include miRNAs controlling T cell stability andplasticity (eg,Tregs, miR-10a) and Th2 cytokine production (eg, miR-92a-3p and miR-423-5p). 34 miRNAs were differentially expressedeight weeks after the end of the treatment, of which 24 (70%)showed similar expression changes at the end of treatment.Conclusions:EPIT leads to homogeneous changes in miRNAexpression profiles shortly after the initiation of treatment differenti-ating EPIT-treated mice from sham-treated control mice and expres-sion changes are maintained following the termination of treatment.Differentially expressed miRNAs include miRNAs in T cell plasticityand postulated targets include genes previously associated withallergy and asthma. Our study provides further evidence for themolecular alterations underlying sustained unresponsiveness in EPIT

Gata3

International audienceBackground Epicutaneous immunotherapy (EPIT) is a promising method for treating food allergies. In animal models, EPIT induces sustained unresponsiveness and prevents further sensitization mediated by Tregs. Here, we elucidate the mechanisms underlying the therapeutic effect of EPIT, by characterizing the kinetics of DNA methylation changes in sorted cells from spleen and blood and by evaluating its persistence and bystander effect compared to oral immunotherapy (OIT). Methods BALB/c mice orally sensitized to peanut proteins (PPE) were treated by EPIT using a PPE-patch or by PPE-OIT. Another set of peanut-sensitized mice treated by EPIT or OIT were sacrificed following a protocol of sensitization to OVA. DNA methylation was analyzed during immunotherapy and 8 weeks after the end of treatment in sorted cells from spleen and blood by pyrosequencing. Humoral and cellular responses were measured during and after immunotherapy. Results Analyses showed a significant hypermethylation of the Gata3 promoter detectable only in Th2 cells for EPIT from the 4th week and a significant hypomethylation of the Foxp3 promoter in CD62L+ Tregs, which was sustained only for EPIT. In addition, mice treated with EPIT were protected from subsequent sensitization and maintained the epigenetic signature characteristic for EPIT. Conclusions Our study demonstrates that EPIT leads to a unique and stable epigenetic signature in specific T-cell compartments with downregulation of Th2 key regulators and upregulation of Treg transcription factors, likely explaining the sustainability of protection and the observed bystander effect

Epicutaneous allergen application preferentially boosts specific T cell responses in sensitized patients

Abstract The effects of epicutaneous allergen administration on systemic immune responses in allergic and non-allergic individuals has not been investigated with defined allergen molecules. We studied the effects of epicutaneous administration of rBet v 1 and rBet v 1 fragments on systemic immune responses in allergic and non-allergic subjects. We conducted a clinical trial in which rBet v 1 and two hypoallergenic rBet v 1 fragments were applied epicutaneously by atopy patch testing (APT) to 15 birch pollen (bp) allergic patients suffering from atopic dermatitis, 5 bp-allergic patients suffering from rhinoconjunctivitis only, 5 patients with respiratory allergy without bp allergy and 5 non-allergic individuals. Epicutaneous administration of rBet v 1 and rBet v 1 fragments led to strong and significant increases of allergen-specific T cell proliferation (CLA+ and CCR4+T cell responses) only in bp-allergic patients with a positive APT reaction. There were no relevant changes of Bet v 1-specific IgE and IgG responses. No changes were noted in allergic subjects without bp allergy and in non-allergic subjects. Epicutaneous allergen application boosts specific T cell but not antibody responses mainly in allergic, APT-positive patients suggesting IgE-facilitated allergen presentation as mechanism for its effects on systemic allergen-specific immune responses