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A Phase I Randomized Therapeutic MVA-B Vaccination Improves the Magnitude and Quality of the T Cell Immune Responses in HIV-1-Infected Subjects on HAART

  • Gómez, Carmen Elena
  • Perdiguero, Beatriz
  • García-Arriaza, Juan
  • Cepeda, Victoria
  • Sánchez-Sorzano, Carlos Óscar
  • Mothe, Beatriz
  • Jiménez, José Luis
  • Muñoz-Fernández, María Ángeles
  • Gatell, José María
  • López Bernaldo de Quirós, Juan Carlos
  • Brander, Christian
  • García, Felipe
  • Esteban, Mariano
  • Universitat Autònoma de Barcelona
TRIAL DESIGN: Previous studies suggested that poxvirus-based vaccines might be instrumental in the therapeutic HIV field. A phase I clinical trial was conducted in HIV-1-infected patients on highly active antiretroviral therapy (HAART), with CD4 T cell counts above 450 cells/mm3 and undetectable viremia. Thirty participants were randomized (2:1) to receive either 3 intramuscular injections of MVA-B vaccine (coding for clade B HIV-1 Env, Gag, Pol and Nef antigens) or placebo,followed by interruption of HAART. METHODS: The magnitude, breadth, quality and phenotype of the HIV-1-specific T cell response were assayed by intracellular cytokine staining (ICS) in 22 volunteers pre- and post-vaccination. RESULTS: MVA-B vaccine induced newly detected HIV-1-specific CD4 T cell responses and expanded pre-existing responses (mostly against Gag, Pol and Nef antigens) that were high in magnitude, broadly directed and showed an enhanced polyfunctionality with a T effector memory (TEM) phenotype, while maintaining the magnitude and quality of the pre-existing HIV-1-specific CD8 T cell responses. In addition, vaccination also triggered preferential CD8+ T cell polyfunctional responses to the MVA vector antigens that increase in magnitude after two and three booster doses. CONCLUSION: MVA-B vaccination represents a feasible strategy to improve T cell responses in individuals with pre-existing HIV-1-specific immunity. TRIAL REGISTRATION: ClinicalTrials. gov NCT01571466.
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Human MAMLD1 Gene Variations Seem Not Sufficient to Explain a 46,XY DSD Phenotype

  • Camats Tarruella, Núria
  • Fernández-Cancio, Mónica
  • Audí, Laura
  • Mullis, Primus E.
  • Moreno, Francisca
  • González Casado, Isabel
  • López-Siguero, Juan Pedro
  • Corripio Collado, Raquel
  • Bermúdez de la Vega, José Antonio
  • Blanco, José Antonio
  • Flück, Christa E.
  • Universitat Autònoma de Barcelona
Ajuts: Swiss National Science Foundation (320030-146127), the Instituto de Salud Carlos III CIBERER U-712, i the University and Research Management and Evaluation Agency (2009SGR31), MAMLD1 is thought to cause disordered sex development in 46,XY patients. But its role is controversial because some MAMLD1 variants are also detected in normal individuals, several MAMLD1 mutations have wild-type activity in functional tests, and the male Mamld1-knockout mouse has normal genitalia and reproduction. Our aim was to search for MAMLD1 variations in 108 46,XY patients with disordered sex development, and to test them functionally. We detected MAMDL1 variations and compared SNP frequencies in controls and patients. We tested MAMLD1 transcriptional activity on promoters involved in sex development and assessed the effect of MAMLD1 on androgen production. MAMLD1 expression in normal steroid-producing tissues and mutant MAMLD1 protein expression were also assessed. Nine MAMLD1 mutations (7 novel) were characterized. In vitro, most MAMLD1 variants acted similarly to wild type. Only the L210X mutation showed loss of function in all tests. We detected no effect of wild-type or MAMLD1 variants on CYP17A1 enzyme activity in our cell experiments, and Western blots revealed no significant differences for MAMLD1 protein expression. MAMLD1 was expressed in human adult testes and adrenals. In conclusion, our data support the notion that MAMLD1 sequence variations may not suffice to explain the phenotype in carriers and that MAMLD1 may also have a role in adult life.
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HIV Testing and Diagnosis Rates in Kiev, Ukraine: April 2013-March 2014

  • Simmons, Ruth
  • Malyuta, Ruslan
  • Chentsova, Nelli
  • Medoeva, Antonia
  • Kruglov, Yuri
  • Yurchenko, Alexander
  • Copas, Andrew
  • Porter, Kholoud
  • CASCADE Collaboration in EuroCoord
Data from Ukraine on risk factors for HIV acquisition are limited. We describe the characteristics of individuals testing for HIV in the main testing centres of the Ukrainian capital Kiev, including HIV risk factors, testing rates, and positivity rates. As part of a larger study to estimate HIV incidence within Kiev City, we included questions on possible risk factors for HIV acquisition and testing history to existing systems in 4 infectious disease clinics. Data were provided by the person requesting an HIV test using a handheld electronic tablet. All persons (≥16 yrs) presenting for an HIV test April 2013-March 2014 were included. Rates per 100,000 were calculated using region-specific denominators for Kiev. During the study period 6370 individuals tested for HIV, equivalent to a testing rate of 293.2 per 100,000. Of these, 467 (7.8%) were HIV-positive, with the highest proportion positive among 31-35 year olds (11.2%), males (9.4%), people who inject drugs (PWID) (17.9%) and men who have sex with men (MSM) (24.1%). Using published population size estimates of MSM, diagnosis rates for MSM ranged from 490.6 to 1548.3/100,000. A higher proportion of heterosexual women compared to heterosexual men reported contact with PWID, (16% vs. 4.7%) suggesting a bridging in risk between PWID and their sexual partners. Collection of HIV risk factor information in Kiev, essential for the purposes of developing effective HIV prevention and response tools, is feasible. The high percentage of MSM among those testing positive for HIV, may indicate a significant level of undisclosed sex between men in national figures.
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The Effect of Incidental Consolidation on Management and Outcomes in COPD Exacerbations: Data from the European COPD Audit

  • Saleh, Aarash
  • López Campos, José Luis
  • Hartl, Sylvia
  • Pozo Rodríguez, Francisco
  • Roberts, Michael
  • European COPD Audit team
There is controversy regarding the significance of radiological consolidation in the context of COPD exacerbation (eCOPD). While some studies into eCOPD exclude these cases, consolidation is a common feature of eCOPD admissions in real practice. This study aims to address the question of whether consolidation in eCOPD is a distinct clinical phenotype with implications for management decisions and outcomes. The European COPD Audit was carried out in 384 hospitals from 13 European countries between 2010 and 2011 to analyze guideline adherence in eCOPD. In this analysis, admissions were split according to the presence or not of consolidation on the admission chest radiograph. Groups were compared in terms of clinical and epidemiological features, existing treatment, clinical care utilized and mortality. RESULTS:14,111 cases were included comprising 2,714 (19.2%) with consolidation and 11,397 (80.8%) without. The risk of radiographic consolidation increased with age, female gender, cardiovascular diseases, having had two or more admissions in the previous year, and sputum color change. Previous treatment with inhaled steroids was not associated. Patients with radiographic consolidation were significantly more likely to receive antibiotics, oxygen and non-invasive ventilation during the admission and had a lower survival from admission to 90-day follow-up. Patients admitted for COPD exacerbation who have radiological consolidation have a more severe illness course, are treated more intensively by clinicians and have a poorer prognosis. We recommend that these patients be considered a distinct subset in COPD exacerbation.
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A Follow-Up of the Multicenter Collaborative Study on HIV-1 Drug Resistance and Tropism Testing Using 454 Ultra Deep Pyrosequencing

  • Saint John, Elizabeth P.
  • Simen, Birgitte B.
  • Turenchalk, Gregory S.
  • Braverman, Michael S.
  • Abbate, Isabella
  • Aerssens, Jeroen
  • Bouchez, Olivier
  • Gabriel, Christian
  • Izopet, Jacques
  • Meixenberger, Karolin
  • Di Giallonardo, Francesca
  • Schlapbach, Ralph
  • Paredes, Roger
  • Sakwa, James
  • Schmitz-Agheguian, Gudrun G.
  • Thielen, Alexander
  • Victor, Martin
  • Metzner, Karin J.
  • Däumer, Martin P.
  • 454 HIV-1 Alpha Study Group
Ultra deep sequencing is of increasing use not only in research but also in diagnostics. For implementation of ultra deep sequencing assays in clinical laboratories for routine diagnostics, intra- and inter-laboratory testing are of the utmost importance. 5A multicenter study was conducted to validate an updated assay design for 454 Life Sciences' GS FLX Titanium system targeting protease/reverse transcriptase (RTP) and env (V3) regions to identify HIV-1 drug-resistance mutations and determine co-receptor use with high sensitivity. The study included 30 HIV-1 subtype B and 6 subtype non-B samples with viral titers (VT) of 3,940-447,400 copies/mL, two dilution series (52,129-1,340 and 25,130-734 copies/mL), and triplicate samples. Amplicons spanning PR codons 10-99, RT codons 1-251 and the entire V3 region were generated using barcoded primers. Analysis was performed using the GS Amplicon Variant Analyzer and geno2pheno for tropism. For comparison, population sequencing was performed using the ViroSeq HIV-1 genotyping system. The median sequencing depth across the 11 sites was 1,829 reads per position for RTP (IQR 592-3,488) and 2,410 for V3 (IQR 786-3,695). 10 preselected drug resistant variants were measured across sites and showed high inter-laboratory correlation across all sites with data (P<0.001). The triplicate samples of a plasmid mixture confirmed the high inter-laboratory consistency (mean% ± stdev: 4.6 ±0.5, 4.8 ±0.4, 4.9 ±0.3) and revealed good intra-laboratory consistency (mean% range ± stdev range: 4.2-5.2 ± 0.04-0.65). In the two dilutions series, no variants >20% were missed, variants 2-10% were detected at most sites (even at low VT), and variants 1-2% were detected by some sites. All mutations detected by population sequencing were also detected by UDS. This assay design results in an accurate and reproducible approach to analyze HIV-1 mutant spectra, even at variant frequencies well below those routinely detectable by population sequencing.
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Identification of effective subdominant anti-HIV-1 CD8+ T cells within entire post-infection and post-vaccination immune responses

  • Hancock, Gemma
  • Yang, Hongbing
  • Yorke, Elisabeth
  • Wainwright, Emma
  • Bourne, Victoria
  • Frisbee, Alyse
  • Payne, Tamika L.
  • Berrong, Mark
  • Ferrari, Guido
  • Chopera, Denis
  • Hanke, Tomas
  • Mothe, Beatriz
  • Brander, Christian
  • McElrath, M. Juliana
  • McMichael, Andrew
  • Goonetilleke, Nilu
  • Tomaras, Georgia D.
  • Frahm, Nicole
  • Dorrell, Lucy
Ajuts: R01/R56 NIH Grant AI-52779 (GDT), NIH F31 Fellowship (1F31AI106519-01)(TLP), Center for AIDS Research (P30 AI 64518) i Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery, grant number UM1-AI100645-01 (AM), Abstract.Defining the components of an HIV immunogen that could induce effective CD8+ T cell responses is critical to vaccine development. We addressed this question by investigating the viral targets of CD8+ T cells that potently inhibit HIV replication in vitro, as this is highly predictive of virus control in vivo. We observed broad and potent ex vivo CD8+ T cell-mediated viral inhibitory activity against a panel of HIV isolates among viremic controllers (VC, viral loads <5000 copies/ml), in contrast to unselected HIV-infected HIV Vaccine trials Network (HVTN) participants. Viral inhibition of clade-matched HIV isolates was strongly correlated with the frequency of CD8+ T cells targeting vulnerable regions within Gag, Pol, Nef and Vif that had been identified in an independent study of nearly 1000 chronically infected individuals. These vulnerable and so-called "beneficial" regions were of low entropy overall, yet several were not predicted by stringent conservation algorithms. Consistent with this, stronger inhibition of clade-matched than mismatched viruses was observed in the majority of subjects, indicating better targeting of clade-specific than conserved epitopes. The magnitude of CD8+ T cell responses to beneficial regions, together with viral entropy and HLA class I genotype, explained up to 59% of the variation in viral inhibitory activity, with magnitude of the T cell response making the strongest unique contribution. However, beneficial regions were infrequently targeted by CD8+ T cells elicited by vaccines encoding full-length HIV proteins, when the latter were administered to healthy volunteers and HIV-positive ART-treated subjects, suggesting that immunodominance hierarchies undermine effective anti-HIV CD8+ T cell responses. Taken together, our data support HIV immunogen design that is based on systematic selection of empirically defined vulnerable regions within the viral proteome, with exclusion of immunodominant decoy epitopes that are irrelevant for HIV control.
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Discordant Impact of HLA on Viral Replicative Capacity and Disease Progression in Pediatric and Adult HIV Infection

  • Adland, Emily
  • Paioni, Paolo
  • Thobakgale, Christina
  • Laker, Leana
  • Mori, Luisa
  • Muenchhoff, Maximilian
  • Csala, Anna
  • Clapson, Margaret
  • Flynn, Jacquie
  • Novelli, Vas
  • Hurst, Jacob
  • Naidoo, Vanessa
  • Shapiro, Roger
  • Gary, Kuan-Hsiang Huang
  • Frater, John
  • Prendergast, Andrew
  • Prado, Julia G.
  • Ndung'u, Thumbi
  • Walker, Bruce D.
  • Carrington, Mary
  • Jooste, Pieter
  • Goulder, Philip J. R.
Ajuts: Wellcome Trust (WT104748MA, PJRG), South African DST/NRF Research Chairs Initiative, Victor Daitz Foundation, International Early Career Scientist Award i Miguel Servet Contract (MS09/00279), Abstract. HLA class I polymorphism has a major influence on adult HIV disease progression. An important mechanism mediating this effect is the impact on viral replicative capacity (VRC) of the escape mutations selected in response to HLA-restricted CD8+ T-cell responses. Factors that contribute to slow progression in pediatric HIV infection are less well understood. We here investigate the relationship between VRC and disease progression in pediatric infection, and the effect of HLA on VRC and on disease outcome in adult and pediatric infection. Studying a South African cohort of >350 ART-naïve, HIV-infected children and their mothers, we first observed that pediatric disease progression is significantly correlated with VRC. As expected, VRCs in mother-child pairs were strongly correlated (p = 0.004). The impact of the protective HLA alleles, HLA-B*57, HLA-B*58:01 and HLA-B*81:01, resulted in significantly lower VRCs in adults (p<0.0001), but not in children. Similarly, in adults, but not in children, VRCs were significantly higher in subjects expressing the disease-susceptible alleles HLA-B*18:01/45:01/58:02 (p = 0.007). Irrespective of the subject, VRCs were strongly correlated with the number of Gag CD8+ T-cell escape mutants driven by HLA-B*57/58:01/81:01 present in each virus (p = 0.0002). In contrast to the impact of VRC common to progression in adults and children, the HLA effects on disease outcome, that are substantial in adults, are small and statistically insignificant in infected children. These data further highlight the important role that VRC plays both in adult and pediatric progression, and demonstrate that HLA-independent factors, yet to be fully defined, are predominantly responsible for pediatric non-progression
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HIV-1 immune activation induces Siglec-1 expression and enhances viral trans-infection in blood and tissue myeloid cells

  • Pino, Maria
  • Erkizia, Itziar
  • Benet, Susana
  • Erikson, Elina
  • Fernández Figueras, Maria Teresa
  • Guerrero, Dolores
  • Dalmau, Judith
  • Ouchi, Dan
  • Rausell, Antonio
  • Ciuffi, Angela
  • Keppler, Oliver T.
  • Telenti, Amalio
  • Kräusslich, Hans-Georg
  • Martínez Picado, Francisco Javier
  • Izquierdo Useros, Nuria
  • Universitat Autònoma de Barcelona
Altres ajuts: Red Temática Cooperativa de Investigación en SIDA (RD06/0006) i Mathilde Krim Fellowship in basic biomedical research 108676, Myeloid cells are key players in the recognition and response of the host against invading viruses. Paradoxically, upon HIV-1 infection, myeloid cells might also promote viral pathogenesis through trans-infection, a mechanism that promotes HIV-1 transmission to target cells via viral capture and storage. The receptor Siglec-1 (CD169) potently enhances HIV-1 trans-infection and is regulated by immune activating signals present throughout the course of HIV-1 infection, such as interferon α (IFNα). Here we show that IFNα-activated dendritic cells, monocytes and macrophages have an enhanced ability to capture and trans-infect HIV-1 via Siglec-1 recognition of viral membrane gangliosides. Monocytes from untreated HIV-1-infected individuals trans-infect HIV-1 via Siglec-1, but this capacity diminishes after effective antiretroviral treatment. Furthermore, Siglec-1 is expressed on myeloid cells residing in lymphoid tissues, where it can mediate viral trans-infection. Siglec-1 on myeloid cells could fuel novel CD4(+) T-cell infections and contribute to HIV-1 dissemination in vivo.
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Variants in the CYP7B1 gene region do not affect natural resistance to HIV-1 infection

  • Sironi, Manuela
  • Biasin, Mara
  • Pontremoli, Chiara
  • Cagliani, Rachele
  • Saulle, Irma
  • Trabattoni, Daria
  • Vichi, Francesca
  • Lo Caputo, Sergio
  • Mazzotta, Francesco
  • Aguilar-Jimenez, Wbeimar
  • Rugeles, María Teresa
  • Cedeno, Samandhy
  • Sanchez, Jorge
  • Brander, Christian
  • Clerici, Mario
  • Universitat Autònoma de Barcelona
Ajuts: Estrategia de Sostenibilidad 2014-2015 de la Universidad de Antioquia, NIH‑NIDCR R01 DE018925‑04, HIVACAT program i CUTHIVAC 241904, Abstract.BACKGROUND: The genetic bases of natural resistance to HIV-1 infection remain largely unknown. Recently, two genome-wide association studies suggested a role for variants within or in the vicinity of the CYP7B1 gene in modulating HIV susceptibility. CYP7B1 is an appealing candidate for this due to its contribution to antiviral immune responses. We analyzed the frequency of two previously described CYP7B1 variants (rs6996198 and rs10808739) in three independent cohorts of HIV-1 infected subjects and HIV-1 exposed seronegative individuals (HESN). FINDINGS:rs6996198 and rs10808739 were genotyped in three case/control cohorts of sexually-exposed HESN and HIV-1-infected individuals from Italy, Peru and Colombia. Comparison of the allele and genotype frequencies of the two SNPs under different models showed that the only significant difference was seen for rs6996198 in the Peruvian sample (nominal p = 0.048, dominant model). For this variant, a random-effect meta-analysis yielded non-significant results (dominant model, p = 0.78) and revealed substantial heterogeneity among cohorts. No significant effect of the rs10808739 allelic status on HIV-1 infection susceptibility (additive model, p = 0.30) emerged from the meta-analysis.CONCLUSIONS: Although our study had limited power to detect association due to the small sample size, comparisons among the three cohorts revealed very similar allelic and genotypic frequencies in HESN and HIV-1 positive subjects. Overall, these data indicate that the two GWAS-defined variants in the CYP7B1 region do not strongly influence HIV-1 infection susceptibility.
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The small RNA content of human sperm reveals pseudogene-derived piRNAs complementary to protein-coding genes

  • Pantano, Lorena
  • Jodar, Meritxell
  • Bak, Mads
  • Ballescà, Josep Lluís
  • Tommerup, Niels
  • Oliva, Rafael
  • Vavouri, Tanya
Altres ajuts: MICINN grant BFU2011-30246, Ramon y Cajal grant RYC-2010-07114, European Commission Framework 7 European Re-integration grant PERG08-GA-2010-276741, Institute of Predictive and Personalized Medicine of Cancer (IMPPC), Danish Council for Independent Research (Technology and Production Sciences), The Lundbeck Foundation, Fundación Salud 2000 SERONO 13-01 i European Commission training network grant (FP7-PEOPLE-2011-ITN289880), Abstract.At the end of mammalian sperm development, sperm cells expel most of their cytoplasm and dispose of the majority of their RNA. Yet, hundreds of RNA molecules remain in mature sperm. The biological significance of the vast majority of these molecules is unclear. To better understand the processes that generate sperm small RNAs and what roles they may have, we sequenced and characterized the small RNA content of sperm samples from two human fertile individuals. We detected 182 microRNAs, some of which are highly abundant. The most abundant microRNA in sperm is miR-1246 with predicted targets among sperm-specific genes. The most abundant class of small noncoding RNAs in sperm are PIWI-interacting RNAs (piRNAs). Surprisingly, we found that human sperm cells contain piRNAs processed from pseudogenes. Clusters of piRNAs from human testes contain pseudogenes transcribed in the antisense strand and processed into small RNAs. Several human protein-coding genes contain antisense predicted targets of pseudogene-derived piRNAs in the male germline and these piRNAs are still found in mature sperm. Our study provides the most extensive data set and annotation of human sperm small RNAs to date and is a resource for further functional studies on the roles of sperm small RNAs. In addition, we propose that some of the pseudogene-derived human piRNAs may regulate expression of their parent gene in the male germline.© 2015 Pantano et al.; Published by Cold Spring Harbor Laboratory Press for the RNA Society.
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