Monocytes Phenotype and cytokine Production in human immunodeficiency Virus-1 infected Patients receiving a Modified Vaccinia ankara-Based hiV-1 Vaccine: relationship to cD300 Molecules expression

A modified vaccinia Ankara-based HIV-1 vaccine clade B (MVA-B) has been tested for safety and immunogenicity in low-risk human immunodeficiency virus (HIV)-uninfected individuals and as a therapeutic vaccine in HIV-1-infected individuals on combined antiretroviral therapy (cART). As a therapeutic vaccine, MVA-B was safe and broadly immunogenic; however, patients still showed a viral rebound upon treatment interruption. Monocytes are an important part of the viral reservoir and several studies suggest that they are partly responsible for the chronic inflammation observed in cART-treated HIV-infected people. The CD300 family of receptors has an important role in several diseases, including viral infections. Monocytes express CD300a, c, e, and f molecules and lipopolysaccharide (LPS) and other stimuli regulate their expression. However, the expression and function of CD300 receptors on monocytes in HIV infection is still unknown. In this work, we investigated for the first time the expression of CD300 molecules and the cytokine production in response to LPS on monocytes from HIV-1-infected patients before and after vaccination with MVA-B. Our results showed that CD300 receptors expression on monocytes from HIV-1-infected patients correlates with markers of HIV infection progression and immune inflammation. Specifically, we observed a positive correlation between the expression of CD300e and CD300f receptors on monocytes with the number of CD4+ T cells of HIV-1-infected patients before vaccination. We also saw a positive correlation between the expression of the inhibitory receptor CD300f and the expression of CD163 on monocytes from HIV-1-infected individuals before and after vaccination. In addition, monocytes exhibited a higher cytokine production in response to LPS after vaccination, almost at the same levels of monocytes from healthy donors. Furthermore, we also described a correlation in the expression of CD300e and CD300f receptors with TNF-α production in response to LPS, only in monocytes of HIV-1-infected patients before vaccination. Altogether, our results describe the impact of HIV-1 and of the MVA-B vaccine in cytokine production and monocytes phenotype.This study was supported by grants from “Plan Estatal de I+ D+ I 2013–2016, ISCIII-Subdirección de Evaluación y Fomento de la Investigación-Fondo Europeo de Desarrollo Regional (FEDER) (Grants PI13/00889, PI15/00480), and Marie Curie Actions, Career Integration Grant, European Commission (Grant CIG 631674).” The study was also partially supported by grants: EC10-153, TRA-094, SAF2015-66193-R,RIS [Red Temática Cooperativa de Grupos de Investigación en Sida del Fondo de Investigación Sanitaria (FIS)], HIVACAT (Catalan Program for the development of HIV-1 vaccines). JV is recipient of a predoctoral contract from the Department of Education, Language Policy, and Culture, Basque Government and a fellowship from the Jesús de Gangoiti Barrera Foundation

Intact IL-12 signaling is necessary for the generation of human natural killer cells with enhanced effector function after restimulation

In this study we tested the role of IL-12–mediated signals in the in vitro generation of human NK cells with enhanced effector function after restimulation. In our opinion the best method to address this issue would involve the use of PBMCs from patients with a deficiency in IL-12 or IL-12 receptor (IL-12R) because we could then exclude that the NK cells used in the experiments had been activated at any time in vivo by IL-12.Supported by the intramural programs of the US Food and Drug Administration and the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, and by the Health Department, Basque Government (Grant 2013111034)

CD300a inhibits CD16-mediated NK cell effector functions in HIV-1-infected patients

Natural killer (NK) cell-mediated antibody-dependent cellular cytotoxicity (ADCC) through CD16 has a critical role in anti-human immunodeficiency virus (HIV) responses. CD300a, an inhibitory receptor highly expressed on NK cells, has the capacity to diminish NK cell killing of pseudorabies-infected cells. CD300a expression is altered during HIV-1 infection on B cells and CD4+ T lymphocytes. In this work, we have investigated in a cross-sectional study the expression and function of CD300a on NK cells from healthy donors, untreated HIV-1 infected subjects and patients on combined antiretroviral treatment (cART). First, we detected an expansion of a CD300a-expressing CD56neg NK cell subset in untreated HIV-1 infected patients. In addition, an association between CD300a expression and other NK cell surface receptors was observed in both healthy and HIV-1 infected people. Notably, we also described that CD300a exerted an inhibitory effect in CD16-mediated effector functions, including degranulation and cytokine production, in all donors and NK cell subsets and, more importantly, this inhibitory effect was higher in HIV-1 infected patients. Therefore, the CD300a inhibitory receptor could be proposed as a new target for therapies aimed to improve NK cells effector functions in HIV-1 infected patients

CD300a identifies a CD4R memory T cell subset with a higher susceptibility to HIV-1 infection

Human CD300a is known to promote the infection by dengue and other enveloped viruses and is overexpressed on CD4R T cells from HIV-1-infected patients.We found that infected CD4RRAS T cells from untreated HIV-1-infected patients were mostly CD300aR. Furthermore, CD300a expressing CD4RRAS T cells from healthy donors were significantly more infected by HIV-1 in vitro than CD300aS cells. CD300a might represent a biomarker of susceptibility to HIV-1 infection on memory CD4R T lymphocytes.The study was supported by a grant from ‘Plan Estatal de IþDþI 2013–2016, ISCIII-Subdirección de Evaluación y Fomento de la Investigación-Fondo Europeo de Desarrollo Regional (FEDER) (Grant PI13/00889)’ and Marie Curie Actions, Career Integration Grant, European Commission (Grant CIG 631674)

Role of age and comorbidities in mortality of patients with infective endocarditis

Purpose: The aim of this study was to analyse the characteristics of patients with IE in three groups of age and to assess the ability of age and the Charlson Comorbidity Index (CCI) to predict mortality. Methods: Prospective cohort study of all patients with IE included in the GAMES Spanish database between 2008 and 2015. Patients were stratified into three age groups:<65 years, 65 to 80 years, and = 80 years.The area under the receiver-operating characteristic (AUROC) curve was calculated to quantify the diagnostic accuracy of the CCI to predict mortality risk. Results: A total of 3120 patients with IE (1327 < 65 years;1291 65-80 years;502 = 80 years) were enrolled.Fever and heart failure were the most common presentations of IE, with no differences among age groups.Patients =80 years who underwent surgery were significantly lower compared with other age groups (14.3%, 65 years; 20.5%, 65-79 years; 31.3%, =80 years). In-hospital mortality was lower in the <65-year group (20.3%, <65 years;30.1%, 65-79 years;34.7%, =80 years;p < 0.001) as well as 1-year mortality (3.2%, <65 years; 5.5%, 65-80 years;7.6%, =80 years; p = 0.003).Independent predictors of mortality were age = 80 years (hazard ratio [HR]:2.78;95% confidence interval [CI]:2.32–3.34), CCI = 3 (HR:1.62; 95% CI:1.39–1.88), and non-performed surgery (HR:1.64;95% CI:11.16–1.58).When the three age groups were compared, the AUROC curve for CCI was significantly larger for patients aged <65 years(p < 0.001) for both in-hospital and 1-year mortality. Conclusion: There were no differences in the clinical presentation of IE between the groups. Age = 80 years, high comorbidity (measured by CCI), and non-performance of surgery were independent predictors of mortality in patients with IE.CCI could help to identify those patients with IE and surgical indication who present a lower risk of in-hospital and 1-year mortality after surgery, especially in the <65-year group

Sunitinib-induced hypertension in CYP3A4 rs4646437 A-allele carriers with metastatic renal cell carcinoma

Experimentele farmacotherapi

Antimicrobial management of Tropheryma whipplei endocarditis: the Spanish Collaboration on Endocarditis (GAMES) experience

OBJECTIVES: Tropheryma whipplei has been detected in 3.5% of the blood culture-negative cases of endocarditis in Spain. Experience in the management of T. whipplei endocarditis is limited. Here we report the long-term outcome of the treatment of previously reported patients who were diagnosed with infective endocarditis (IE) caused by T. whipplei from the Spanish Collaboration on Endocarditis-Grupo de Apoyo al Manejo de la Endocarditis Infecciosa en Espana (GAMES) and discuss potential options for antimicrobial therapy for IE caused by T. whipplei. PATIENTS AND METHODS: Seventeen patients with T. whipplei endocarditis were recruited between 2008 and 2014 in 25 Spanish hospitals. Patients were classified according to the therapeutic regimen: ceftriaxone and trimethoprim/sulfamethoxazole, doxycycline + hydroxychloroquine and other treatment options. RESULTS: Follow-up data were obtained from 14 patients. The median follow-up was 46.5 months. All patients completed the antibiotic treatment prescribed, with a median duration of 13 months. Six patients were treated with ceftriaxone and trimethoprim/sulfamethoxazole (median duration 13 months), four with doxycycline + hydroxychloroquine (median duration 13.8 months) and four with other treatment options (median duration 22.3 months). The follow-up after the end of the treatments was between 5 and 84 months (median 24 months). CONCLUSIONS: All treatment lines were effective and well tolerated. Therapeutic failures were not detected during the treatment. None of the patients died or experienced a relapse during the follow-up. Only six patients received antibiotic treatment in accordance with guidelines. These data suggest that shorter antimicrobial treatments could be effective

Prosthetic Valve Candida spp. Endocarditis: New Insights into Long-term Prognosis-The ESCAPE Study

Background. Prosthetic valve endocarditis caused by Candida spp. (PVE-C) is rare and devastating, with international guidelines based on expert recommendations supporting the combination of surgery and subsequent azole treatment. Methods. We retrospectively analyzed PVE-C cases collected in Spain and France between 2001 and 2015, with a focus on management and outcome. Results. Forty-six cases were followed up for a median of 9 months. Twenty-two patients (48%) had a history of endocarditis, 30 cases (65%) were nosocomial or healthcare related, and 9 (20%) patients were intravenous drug users. "Induction" therapy consisted mainly of liposomal amphotericin B (L-amB)-based (n = 21) or echinocandin-based therapy (n = 13). Overall, 19 patients (41%) were operated on. Patients &lt;66 years old and without cardiac failure were more likely to undergo cardiac surgery (adjusted odds ratios [aORs], 6.80 [95% confdence interval [CI], 1.59-29.13] and 10.92 [1.15-104.06], respectively). Surgery was not associated with better survival rates at 6 months. Patients who received L-amB alone had a better 6-month survival rate than those who received an echinocandin alone (aOR, 13.52; 95% CI, 1.03-838.10). "Maintenance" fluconazole therapy, prescribed in 21 patients for a median duration of 13 months (range, 2-84 months), led to minor adverse effects. Conclusion. L-amB induction treatment improves survival in patients with PVE-C. Medical treatment followed by long-term maintenance fluconazole may be the best treatment option for frail patients