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Search Results: 1 - 10 of 4007 matches for " Jacques Fellay "
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Host Genetics and HIV-1: The Final Phase?
Jacques Fellay ,Kevin V. Shianna,Amalio Telenti,David B. Goldstein
PLOS Pathogens , 2010, DOI: 10.1371/journal.ppat.1001033
Abstract: This is a crucial transition time for human genetics in general, and for HIV host genetics in particular. After years of equivocal results from candidate gene analyses, several genome-wide association studies have been published that looked at plasma viral load or disease progression. Results from other studies that used various large-scale approaches (siRNA screens, transcriptome or proteome analysis, comparative genomics) have also shed new light on retroviral pathogenesis. However, most of the inter-individual variability in response to HIV-1 infection remains to be explained: genome resequencing and systems biology approaches are now required to progress toward a better understanding of the complex interactions between HIV-1 and its human host.
Mapping of positive selection sites in the HIV-1 genome in the context of RNA and protein structural constraints
Joke Snoeck, Jacques Fellay, István Bartha, Daniel C Douek, Amalio Telenti
Retrovirology , 2011, DOI: 10.1186/1742-4690-8-87
Abstract: To build a thorough evolutionary, functional and structural map of the HIV-1 genome, complete subtype B sequences were obtained from the Los Alamos database. We mapped sites under positive selective pressure, amino acid conservation, protein and RNA structure, overlapping coding frames, CD8 T cell, CD4 T cell and antibody epitopes, and sites enriched in AG and AA dinucleotide motives. Globally, 33% of amino acid positions were found to be variable and 12% of the genome was under positive selection. Because interrelated constraining and diversifying forces shape the viral genome, we included the variables from both classes of pressure in a multivariate model to predict conservation or positive selection: structured RNA and α-helix domains independently predicted conservation while CD4 T cell and antibody epitopes were associated with positive selection.The global map of the viral genome contains positive selected sites that are not in canonical CD8 T cell, CD4 T cell or antibody epitopes; thus, it identifies a class of residues that may be targeted by other host selective pressures. Overall, RNA structure represents the strongest determinant of HIV-1 conservation. These data can inform the combined analysis of host and viral genetic information.The HIV-1 genome is highly polymorphic, for several reasons. Firstly, different cross-species transmission events gave rise to different viral lineages in humans [1]. In addition, intrinsic characteristics of the virus, such as its short generation time, and lack of proofreading activity of the reverse transcriptase further increase genetic variability [2]. The virus is capable of genomic recombination, and most of its proteins tolerate coding variation [3,4]. Based on this genetic diversity, HIV-1 can be classified into several types, groups, and subtypes [5].Theoretically, every single mutation at every position in the genome is generated every day. However, most of the resulting virions are not viable, and various layers of
Analysis of Stop-Gain and Frameshift Variants in Human Innate Immunity Genes
Antonio Rausell,Pejman Mohammadi,Paul J. McLaren,Istvan Bartha,Ioannis Xenarios,Jacques Fellay,Amalio Telenti
PLOS Computational Biology , 2014, DOI: doi/10.1371/journal.pcbi.1003757
Abstract: Loss-of-function variants in innate immunity genes are associated with Mendelian disorders in the form of primary immunodeficiencies. Recent resequencing projects report that stop-gains and frameshifts are collectively prevalent in humans and could be responsible for some of the inter-individual variability in innate immune response. Current computational approaches evaluating loss-of-function in genes carrying these variants rely on gene-level characteristics such as evolutionary conservation and functional redundancy across the genome. However, innate immunity genes represent a particular case because they are more likely to be under positive selection and duplicated. To create a ranking of severity that would be applicable to innate immunity genes we evaluated 17,764 stop-gain and 13,915 frameshift variants from the NHLBI Exome Sequencing Project and 1,000 Genomes Project. Sequence-based features such as loss of functional domains, isoform-specific truncation and nonsense-mediated decay were found to correlate with variant allele frequency and validated with gene expression data. We integrated these features in a Bayesian classification scheme and benchmarked its use in predicting pathogenic variants against Online Mendelian Inheritance in Man (OMIM) disease stop-gains and frameshifts. The classification scheme was applied in the assessment of 335 stop-gains and 236 frameshifts affecting 227 interferon-stimulated genes. The sequence-based score ranks variants in innate immunity genes according to their potential to cause disease, and complements existing gene-based pathogenicity scores. Specifically, the sequence-based score improves measurement of functional gene impairment, discriminates across different variants in a given gene and appears particularly useful for analysis of less conserved genes.
Disentangling Human Tolerance and Resistance Against HIV
Roland R. Regoes ,Paul J. McLaren,Manuel Battegay,Enos Bernasconi,Alexandra Calmy,Huldrych F. Günthard,Matthias Hoffmann,Andri Rauch,Amalio Telenti,Jacques Fellay,the Swiss HIV Cohort Study
PLOS Biology , 2014, DOI: 10.1371/journal.pbio.1001951
Abstract: In ecology, “disease tolerance” is defined as an evolutionary strategy of hosts against pathogens, characterized by reduced or absent pathogenesis despite high pathogen load. To our knowledge, tolerance has to date not been quantified and disentangled from host resistance to disease in any clinically relevant human infection. Using data from the Swiss HIV Cohort Study, we investigated if there is variation in tolerance to HIV in humans and if this variation is associated with polymorphisms in the human genome. In particular, we tested for associations between tolerance and alleles of the Human Leukocyte Antigen (HLA) genes, the CC chemokine receptor 5 (CCR5), the age at which individuals were infected, and their sex. We found that HLA-B alleles associated with better HIV control do not confer tolerance. The slower disease progression associated with these alleles can be fully attributed to the extent of viral load reduction in carriers. However, we observed that tolerance significantly varies across HLA-B genotypes with a relative standard deviation of 34%. Furthermore, we found that HLA-B homozygotes are less tolerant than heterozygotes. Lastly, tolerance was observed to decrease with age, resulting in a 1.7-fold difference in disease progression between 20 and 60-y-old individuals with the same viral load. Thus, disease tolerance is a feature of infection with HIV, and the identification of the mechanisms involved may pave the way to a better understanding of pathogenesis.
Privacy in the Genomic Era
Muhammad Naveed,Erman Ayday,Ellen W. Clayton,Jacques Fellay,Carl A. Gunter,Jean-Pierre Hubaux,Bradley A. Malin,XiaoFeng Wang
Computer Science , 2014,
Abstract: Genome sequencing technology has advanced at a rapid pace and it is now possible to generate highly-detailed genotypes inexpensively. The collection and analysis of such data has the potential to support various applications, including personalized medical services. While the benefits of the genomics revolution are trumpeted by the biomedical community, the increased availability of such data has major implications for personal privacy; notably because the genome has certain essential features, which include (but are not limited to) (i) an association with traits and certain diseases, (ii) identification capability (e.g., forensics), and (iii) revelation of family relationships. Moreover, direct-to-consumer DNA testing increases the likelihood that genome data will be made available in less regulated environments, such as the Internet and for-profit companies. The problem of genome data privacy thus resides at the crossroads of computer science, medicine, and public policy. While the computer scientists have addressed data privacy for various data types, there has been less attention dedicated to genomic data. Thus, the goal of this paper is to provide a systematization of knowledge for the computer science community. In doing so, we address some of the (sometimes erroneous) beliefs of this field and we report on a survey we conducted about genome data privacy with biomedical specialists. Then, after characterizing the genome privacy problem, we review the state-of-the-art regarding privacy attacks on genomic data and strategies for mitigating such attacks, as well as contextualizing these attacks from the perspective of medicine and public policy. This paper concludes with an enumeration of the challenges for genome data privacy and presents a framework to systematize the analysis of threats and the design of countermeasures as the field moves forward.
Dynamics of HIV Latency and Reactivation in a Primary CD4+ T Cell Model
Pejman Mohammadi equal contributor,Julia di Iulio equal contributor,Miguel Mu?oz,Raquel Martinez,István Bartha,Matthias Cavassini,Christian Thorball,Jacques Fellay,Niko Beerenwinkel ,Angela Ciuffi ,Amalio Telenti
PLOS Pathogens , 2014, DOI: doi/10.1371/journal.ppat.1004156
Abstract: HIV latency is a major obstacle to curing infection. Current strategies to eradicate HIV aim at increasing transcription of the latent provirus. In the present study we observed that latently infected CD4+ T cells from HIV-infected individuals failed to produce viral particles upon ex vivo exposure to SAHA (vorinostat), despite effective inhibition of histone deacetylases. To identify steps that were not susceptible to the action of SAHA or other latency reverting agents, we used a primary CD4+ T cell model, joint host and viral RNA sequencing, and a viral-encoded reporter. This model served to investigate the characteristics of latently infected cells, the dynamics of HIV latency, and the process of reactivation induced by various stimuli. During latency, we observed persistence of viral transcripts but only limited viral translation. Similarly, the reactivating agents SAHA and disulfiram successfully increased viral transcription, but failed to effectively enhance viral translation, mirroring the ex vivo data. This study highlights the importance of post-transcriptional blocks as one mechanism leading to HIV latency that needs to be relieved in order to purge the viral reservoir.
Oral Postdialysis Cholecalciferol Supplementation in Patients on Maintenance Hemodialysis: A Dose-Response Approach
Eric Descombes,Benoit Fellay,Ould Maouloud Hemett,Jean-Luc Magnin,Gilbert Fellay
International Journal of Nephrology , 2014, DOI: 10.1155/2014/597429
Abstract: The aim of the present study was to evaluate the dose of postdialysis cholecalciferol needed to maintain the 25-hydroxyvitamin D [25(OH)D] levels in the optimal range of 75–150?nmol/L. Twenty-six patients who had low baseline 25(OH)D levels (mean ?nmol/L) were studied. The 25(OH)D levels were measured every 2 months for one year. During the first two months, all the patients received 2000?IU of cholecalciferol after each hemodialysis (=6000?IU/wk). Thereafter, the dose was individualized and adapted every 2 months by administering 1 to 6 cholecalciferol tablets (2000?IU each) per week (total weekly dose = 2000–12000?IU/wk). During cholecalciferol supplementation, the 25(OH)D concentrations rapidly increased from baseline to ?nmol/L at month 6 and ?nmol/L at month 12. At month twelve, 86% of the patients had 25(OH)D levels within the target range with a mean dose of ?IU/wk of cholecalciferol; however, the amount needed to maintain these levels varied widely from 0 ( ) to 12000?IU/wk ( ). In conclusion, postdialysis cholecalciferol prescription is quite effective in correcting vitamin D deficiency/insufficiency, but the amount of cholecalciferol needed to maintain the 25(OH)D levels within the optimal range over the long-term varies widely among patients and must be individualized. 1. Introduction Recent important advances have been made in understanding vitamin D physiology, beyond its classic role in mineral and bone metabolism [1–11]. Indeed, recent studies have shown that several tissues, in addition to the kidneys, express the enzyme CYP27B1, which catalyzes the 1 -hydroxylation of 25(OH)D, and that the vitamin D receptor (VDR) is expressed ubiquitously [1–11]. It is now known that a conversion of 25(OH)D to 1 ,25-dihydroxyvitamin D (calcitriol, the active form of vitamin D) occurs in several extrarenal cells and may be associated with significant biological roles beyond those traditionally attributed to vitamin D [1–11]. As a consequence, there has been a great deal of interest in the study of these nonclassical autocrine/intracrine effects of vitamin D during the past few years and a significant body of information in the medical literature has shown that vitamin D deficiency/insufficiency is associated with several abnormalities such as an increased risk of cardiovascular, musculoskeletal and autoimmune diseases, cancer, infections, diabetes, and mortality [1–6, 12–27]. As a result, the possible benefits of vitamin D supplementation in patients with low levels became the focus of interest of the scientific community and studies have even reported
Copy Number Variation of KIR Genes Influences HIV-1 Control
Kimberly Pelak,Anna C. Need,Jacques Fellay,Kevin V. Shianna,Sheng Feng,Thomas J. Urban,Dongliang Ge,Andrea De Luca,Javier Martinez-Picado,Steven M. Wolinsky,Jeremy J. Martinson,Beth D. Jamieson,Jay H. Bream,Maureen P. Martin,Persephone Borrow,Norman L. Letvin,Andrew J. McMichael,Barton F. Haynes,Amalio Telenti,Mary Carrington,David B. Goldstein,Galit Alter
PLOS Biology , 2012, DOI: 10.1371/journal.pbio.1001208
Abstract: A genome-wide screen for large structural variants showed that a copy number variant (CNV) in the region encoding killer cell immunoglobulin-like receptors (KIR) associates with HIV-1 control as measured by plasma viral load at set point in individuals of European ancestry. This CNV encompasses the KIR3DL1-KIR3DS1 locus, encoding receptors that interact with specific HLA-Bw4 molecules to regulate the activation of lymphocyte subsets including natural killer (NK) cells. We quantified the number of copies of KIR3DS1 and KIR3DL1 in a large HIV-1 positive cohort, and showed that an increase in KIR3DS1 count associates with a lower viral set point if its putative ligand is present (p = 0.00028), as does an increase in KIR3DL1 count in the presence of KIR3DS1 and appropriate ligands for both receptors (p = 0.0015). We further provide functional data that demonstrate that NK cells from individuals with multiple copies of KIR3DL1, in the presence of KIR3DS1 and the appropriate ligands, inhibit HIV-1 replication more robustly, and associated with a significant expansion in the frequency of KIR3DS1+, but not KIR3DL1+, NK cells in their peripheral blood. Our results suggest that the relative amounts of these activating and inhibitory KIR play a role in regulating the peripheral expansion of highly antiviral KIR3DS1+ NK cells, which may determine differences in HIV-1 control following infection.
Genome-Wide Association Study Identifies Single Nucleotide Polymorphism in DYRK1A Associated with Replication of HIV-1 in Monocyte-Derived Macrophages
Sebastiaan M. Bol,Perry D. Moerland,Sophie Limou,Yvonne van Remmerden,Cédric Coulonges,Dani?lle van Manen,Joshua T. Herbeck,Jacques Fellay,Margit Sieberer,Jantine G. Sietzema,Ruben van 't Slot,Jeremy Martinson,Jean-Fran?ois Zagury,Hanneke Schuitemaker,Angélique B. van 't Wout
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0017190
Abstract: HIV-1 infected macrophages play an important role in rendering resting T cells permissive for infection, in spreading HIV-1 to T cells, and in the pathogenesis of AIDS dementia. During highly active anti-retroviral treatment (HAART), macrophages keep producing virus because tissue penetration of antiretrovirals is suboptimal and the efficacy of some is reduced. Thus, to cure HIV-1 infection with antiretrovirals we will also need to efficiently inhibit viral replication in macrophages. The majority of the current drugs block the action of viral enzymes, whereas there is an abundance of yet unidentified host factors that could be targeted. We here present results from a genome-wide association study identifying novel genetic polymorphisms that affect in vitro HIV-1 replication in macrophages.
Genome-Wide mRNA Expression Correlates of Viral Control in CD4+ T-Cells from HIV-1-Infected Individuals
Margalida Rotger equal contributor,Kristen K. Dang equal contributor,Jacques Fellay equal contributor,Erin L. Heinzen,Sheng Feng,Patrick Descombes,Kevin V. Shianna,Dongliang Ge,Huldrych F. Günthard,David B. Goldstein ,Amalio Telenti ,The Swiss HIV Cohort Study and the Center for HIV/AIDS Vaccine Immunology
PLOS Pathogens , 2010, DOI: 10.1371/journal.ppat.1000781
Abstract: There is great interindividual variability in HIV-1 viral setpoint after seroconversion, some of which is known to be due to genetic differences among infected individuals. Here, our focus is on determining, genome-wide, the contribution of variable gene expression to viral control, and to relate it to genomic DNA polymorphism. RNA was extracted from purified CD4+ T-cells from 137 HIV-1 seroconverters, 16 elite controllers, and 3 healthy blood donors. Expression levels of more than 48,000 mRNA transcripts were assessed by the Human-6 v3 Expression BeadChips (Illumina). Genome-wide SNP data was generated from genomic DNA using the HumanHap550 Genotyping BeadChip (Illumina). We observed two distinct profiles with 260 genes differentially expressed depending on HIV-1 viral load. There was significant upregulation of expression of interferon stimulated genes with increasing viral load, including genes of the intrinsic antiretroviral defense. Upon successful antiretroviral treatment, the transcriptome profile of previously viremic individuals reverted to a pattern comparable to that of elite controllers and of uninfected individuals. Genome-wide evaluation of cis-acting SNPs identified genetic variants modulating expression of 190 genes. Those were compared to the genes whose expression was found associated with viral load: expression of one interferon stimulated gene, OAS1, was found to be regulated by a SNP (rs3177979, p = 4.9E-12); however, we could not detect an independent association of the SNP with viral setpoint. Thus, this study represents an attempt to integrate genome-wide SNP signals with genome-wide expression profiles in the search for biological correlates of HIV-1 control. It underscores the paradox of the association between increasing levels of viral load and greater expression of antiviral defense pathways. It also shows that elite controllers do not have a fully distinctive mRNA expression pattern in CD4+ T cells. Overall, changes in global RNA expression reflect responses to viral replication rather than a mechanism that might explain viral control.
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