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1.
Nature ; 618(7965): 590-597, 2023 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-37258672

RESUMO

Rapidly evolving influenza A viruses (IAVs) and influenza B viruses (IBVs) are major causes of recurrent lower respiratory tract infections. Current influenza vaccines elicit antibodies predominantly to the highly variable head region of haemagglutinin and their effectiveness is limited by viral drift1 and suboptimal immune responses2. Here we describe a neuraminidase-targeting monoclonal antibody, FNI9, that potently inhibits the enzymatic activity of all group 1 and group 2 IAVs, as well as Victoria/2/87-like, Yamagata/16/88-like and ancestral IBVs. FNI9 broadly neutralizes seasonal IAVs and IBVs, including the immune-evading H3N2 strains bearing an N-glycan at position 245, and shows synergistic activity when combined with anti-haemagglutinin stem-directed antibodies. Structural analysis reveals that D107 in the FNI9 heavy chain complementarity-determinant region 3 mimics the interaction of the sialic acid carboxyl group with the three highly conserved arginine residues (R118, R292 and R371) of the neuraminidase catalytic site. FNI9 demonstrates potent prophylactic activity against lethal IAV and IBV infections in mice. The unprecedented breadth and potency of the FNI9 monoclonal antibody supports its development for the prevention of influenza illness by seasonal and pandemic viruses.


Assuntos
Anticorpos Antivirais , Especificidade de Anticorpos , Vírus da Influenza A , Vírus da Influenza B , Vacinas contra Influenza , Influenza Humana , Mimetismo Molecular , Neuraminidase , Animais , Humanos , Camundongos , Anticorpos Monoclonais/química , Anticorpos Monoclonais/imunologia , Anticorpos Monoclonais/uso terapêutico , Anticorpos Antivirais/química , Anticorpos Antivirais/imunologia , Anticorpos Antivirais/uso terapêutico , Especificidade de Anticorpos/imunologia , Arginina/química , Domínio Catalítico , Hemaglutininas Virais/imunologia , Vírus da Influenza A/classificação , Vírus da Influenza A/enzimologia , Vírus da Influenza A/imunologia , Vírus da Influenza A Subtipo H3N2/enzimologia , Vírus da Influenza A Subtipo H3N2/imunologia , Vírus da Influenza B/classificação , Vírus da Influenza B/enzimologia , Vírus da Influenza B/imunologia , Vacinas contra Influenza/química , Vacinas contra Influenza/imunologia , Vacinas contra Influenza/uso terapêutico , Influenza Humana/imunologia , Influenza Humana/prevenção & controle , Neuraminidase/antagonistas & inibidores , Neuraminidase/química , Neuraminidase/imunologia , Infecções por Orthomyxoviridae/imunologia , Infecções por Orthomyxoviridae/prevenção & controle , Estações do Ano , Ácidos Siálicos/química
2.
Nature ; 620(7976): 1025-1030, 2023 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-37532928

RESUMO

HIV-1 remains a global health crisis1, highlighting the need to identify new targets for therapies. Here, given the disproportionate HIV-1 burden and marked human genome diversity in Africa2, we assessed the genetic determinants of control of set-point viral load in 3,879 people of African ancestries living with HIV-1 participating in the international collaboration for the genomics of HIV3. We identify a previously undescribed association signal on chromosome 1 where the peak variant associates with an approximately 0.3 log10-transformed copies per ml lower set-point viral load per minor allele copy and is specific to populations of African descent. The top associated variant is intergenic and lies between a long intergenic non-coding RNA (LINC00624) and the coding gene CHD1L, which encodes a helicase that is involved in DNA repair4. Infection assays in iPS cell-derived macrophages and other immortalized cell lines showed increased HIV-1 replication in CHD1L-knockdown and CHD1L-knockout cells. We provide evidence from population genetic studies that Africa-specific genetic variation near CHD1L associates with HIV replication in vivo. Although experimental studies suggest that CHD1L is able to limit HIV infection in some cell types in vitro, further investigation is required to understand the mechanisms underlying our observations, including any potential indirect effects of CHD1L on HIV spread in vivo that our cell-based assays cannot recapitulate.


Assuntos
DNA Helicases , Proteínas de Ligação a DNA , Variação Genética , Infecções por HIV , HIV-1 , Carga Viral , Humanos , Linhagem Celular , DNA Helicases/genética , DNA Helicases/metabolismo , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Infecções por HIV/genética , HIV-1/crescimento & desenvolvimento , HIV-1/fisiologia , Carga Viral/genética , África , Cromossomos Humanos Par 1/genética , Alelos , RNA Longo não Codificante/genética , Replicação Viral
3.
Nature ; 597(7874): 103-108, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34280951

RESUMO

The recent emergence of SARS-CoV-2 variants of concern1-10 and the recurrent spillovers of coronaviruses11,12 into the human population highlight the need for broadly neutralizing antibodies that are not affected by the ongoing antigenic drift and that can prevent or treat future zoonotic infections. Here we describe a human monoclonal antibody designated S2X259, which recognizes a highly conserved cryptic epitope of the receptor-binding domain and cross-reacts with spikes from all clades of sarbecovirus. S2X259 broadly neutralizes spike-mediated cell entry of SARS-CoV-2, including variants of concern (B.1.1.7, B.1.351, P.1, and B.1.427/B.1.429), as well as a wide spectrum of human and potentially zoonotic sarbecoviruses through inhibition of angiotensin-converting enzyme 2 (ACE2) binding to the receptor-binding domain. Furthermore, deep-mutational scanning and in vitro escape selection experiments demonstrate that S2X259 possesses an escape profile that is limited to a single substitution, G504D. We show that prophylactic and therapeutic administration of S2X259 protects Syrian hamsters (Mesocricetus auratus) against challenge with the prototypic SARS-CoV-2 and the B.1.351 variant of concern, which suggests that this monoclonal antibody is a promising candidate for the prevention and treatment of emergent variants and zoonotic infections. Our data reveal a key antigenic site that is targeted by broadly neutralizing antibodies and will guide the design of vaccines that are effective against all sarbecoviruses.


Assuntos
Anticorpos Monoclonais/imunologia , Anticorpos Monoclonais/uso terapêutico , Anticorpos Antivirais/imunologia , Anticorpos Amplamente Neutralizantes/imunologia , Anticorpos Amplamente Neutralizantes/uso terapêutico , COVID-19/prevenção & controle , SARS-CoV-2/classificação , SARS-CoV-2/imunologia , Animais , Anticorpos Monoclonais/química , Anticorpos Antivirais/química , Anticorpos Antivirais/uso terapêutico , Anticorpos Amplamente Neutralizantes/química , COVID-19/imunologia , COVID-19/virologia , Reações Cruzadas/imunologia , Modelos Animais de Doenças , Feminino , Humanos , Evasão da Resposta Imune/genética , Evasão da Resposta Imune/imunologia , Mesocricetus/imunologia , Mesocricetus/virologia , Mutação , Testes de Neutralização , SARS-CoV-2/química , SARS-CoV-2/genética , Zoonoses Virais/imunologia , Zoonoses Virais/prevenção & controle , Zoonoses Virais/virologia
4.
Nat Rev Genet ; 19(1): 51-62, 2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-29082913

RESUMO

A gene can be defined as essential when loss of its function compromises viability of the individual (for example, embryonic lethality) or results in profound loss of fitness. At the population level, identification of essential genes is accomplished by observing intolerance to loss-of-function variants. Several computational methods are available to score gene essentiality, and recent progress has been made in defining essentiality in the non-coding genome. Haploinsufficiency is emerging as a critical aspect of gene essentiality: approximately 3,000 human genes cannot tolerate loss of one of the two alleles. Genes identified as essential in human cell lines or knockout mice may be distinct from those in living humans. Reconciling these discrepancies in how we evaluate gene essentiality has applications in clinical genetics and may offer insights for drug development.


Assuntos
Genes Essenciais , Animais , Variação Genética , Genoma Humano , Genômica , Haploinsuficiência , Humanos , Camundongos , Camundongos Knockout , RNA não Traduzido/genética
7.
Proc Natl Acad Sci U S A ; 118(22)2021 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-34031243

RESUMO

The modulation of the transcriptome is among the earliest responses to infection. However, defining the transcriptomic signatures of disease is challenging because logistic, technical, and cost factors limit the size and representativeness of samples in clinical studies. These limitations lead to a poor performance of signatures when applied to new datasets. Although the study focuses on infection, the central hypothesis of the work is the generalization of sets of signatures across diseases. We use a machine learning approach to identify common elements in datasets and then test empirically whether they are informative about a second dataset from a disease or process distinct from the original dataset. We identify sets of genes, which we name transfer signatures, that are predictive across diverse datasets and/or species (e.g., rhesus to humans). We demonstrate the usefulness of transfer signatures in two use cases: the progression of latent to active tuberculosis and the severity of COVID-19 and influenza A H1N1 infection. This indicates that transfer signatures can be deployed in settings that lack disease-specific biomarkers. The broad significance of our work lies in the concept that a small set of archetypal human immunophenotypes, captured by transfer signatures, can explain a larger set of responses to diverse diseases.


Assuntos
Doenças Transmissíveis/genética , Perfilação da Expressão Gênica , Transcriptoma/genética , Bases de Dados Genéticas , Humanos , Tuberculose/genética , Viroses/genética
8.
Proc Natl Acad Sci U S A ; 116(18): 8960-8965, 2019 04 30.
Artigo em Inglês | MEDLINE | ID: mdl-30988206

RESUMO

Sequence variation data of the human proteome can be used to analyze 3D protein structures to derive functional insights. We used genetic variant data from nearly 140,000 individuals to analyze 3D positional conservation in 4,715 proteins and 3,951 homology models using 860,292 missense and 465,886 synonymous variants. Sixty percent of protein structures harbor at least one intolerant 3D site as defined by significant depletion of observed over expected missense variation. Structural intolerance data correlated with deep mutational scanning functional readouts for PPARG, MAPK1/ERK2, UBE2I, SUMO1, PTEN, CALM1, CALM2, and TPK1 and with shallow mutagenesis data for 1,026 proteins. The 3D structural intolerance analysis revealed different features for ligand binding pockets and orthosteric and allosteric sites. Large-scale data on human genetic variation support a definition of functional 3D sites proteome-wide.


Assuntos
Variação Genética/genética , Imageamento Tridimensional/métodos , Proteoma/genética , Sítios de Ligação , Calmodulina/genética , Análise Mutacional de DNA/métodos , Humanos , Ligantes , Proteína Quinase 1 Ativada por Mitógeno/genética , Modelos Moleculares , Conformação Molecular , Mutação , PPAR gama/genética , PTEN Fosfo-Hidrolase/genética , Conformação Proteica , Proteína SUMO-1/genética , Enzimas Ativadoras de Ubiquitina/genética
9.
Proc Natl Acad Sci U S A ; 115(14): 3686-3691, 2018 04 03.
Artigo em Inglês | MEDLINE | ID: mdl-29555771

RESUMO

Reducing premature mortality associated with age-related chronic diseases, such as cancer and cardiovascular disease, is an urgent priority. We report early results using genomics in combination with advanced imaging and other clinical testing to proactively screen for age-related chronic disease risk among adults. We enrolled active, symptom-free adults in a study of screening for age-related chronic diseases associated with premature mortality. In addition to personal and family medical history and other clinical testing, we obtained whole-genome sequencing (WGS), noncontrast whole-body MRI, dual-energy X-ray absorptiometry (DXA), global metabolomics, a new blood test for prediabetes (Quantose IR), echocardiography (ECHO), ECG, and cardiac rhythm monitoring to identify age-related chronic disease risks. Precision medicine screening using WGS and advanced imaging along with other testing among active, symptom-free adults identified a broad set of complementary age-related chronic disease risks associated with premature mortality and strengthened WGS variant interpretation. This and other similarly designed screening approaches anchored by WGS and advanced imaging may have the potential to extend healthy life among active adults through improved prevention and early detection of age-related chronic diseases (and their risk factors) associated with premature mortality.


Assuntos
Doença/genética , Predisposição Genética para Doença , Processamento de Imagem Assistida por Computador/métodos , Mutação , Medicina de Precisão/métodos , Sequenciamento Completo do Genoma/métodos , Adulto , Idoso , Idoso de 80 Anos ou mais , Doenças Cardiovasculares/diagnóstico por imagem , Doenças Cardiovasculares/genética , Doenças Cardiovasculares/patologia , Doença/classificação , Feminino , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias/diagnóstico por imagem , Neoplasias/genética , Neoplasias/patologia , Doenças do Sistema Nervoso/diagnóstico por imagem , Doenças do Sistema Nervoso/genética , Doenças do Sistema Nervoso/patologia , Medição de Risco , Análise de Sequência de RNA , Adulto Jovem
10.
Proc Natl Acad Sci U S A ; 114(31): 8342-8347, 2017 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-28716935

RESUMO

Viral respiratory infections are usually mild and self-limiting; still they exceptionally result in life-threatening infections in previously healthy children. To investigate a potential genetic cause, we recruited 120 previously healthy children requiring support in intensive care because of a severe illness caused by a respiratory virus. Using exome and transcriptome sequencing, we identified and characterized three rare loss-of-function variants in IFIH1, which encodes an RIG-I-like receptor involved in the sensing of viral RNA. Functional testing of the variants IFIH1 alleles demonstrated that the resulting proteins are unable to induce IFN-ß, are intrinsically less stable than wild-type IFIH1, and lack ATPase activity. In vitro assays showed that IFIH1 effectively restricts replication of human respiratory syncytial virus and rhinoviruses. We conclude that IFIH1 deficiency causes a primary immunodeficiency manifested in extreme susceptibility to common respiratory RNA viruses.


Assuntos
Predisposição Genética para Doença/genética , Síndromes de Imunodeficiência/genética , Helicase IFIH1 Induzida por Interferon/genética , Interferon beta/biossíntese , Vírus Sinciciais Respiratórios/imunologia , Infecções Respiratórias/virologia , Rhinovirus/imunologia , Adenosina Trifosfatases/genética , Pré-Escolar , Cuidados Críticos , Feminino , Variação Genética/genética , Humanos , Síndromes de Imunodeficiência/imunologia , Lactente , Recém-Nascido , Interferon beta/imunologia , Masculino , Estudos Prospectivos , Isoformas de Proteínas/genética , Infecções Respiratórias/imunologia , Replicação Viral/imunologia
11.
PLoS Genet ; 12(3): e1005921, 2016 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-26942578

RESUMO

Human APOBEC3 cytidine deaminases are intrinsic resistance factors to HIV-1. However, HIV-1 encodes a viral infectivity factor (Vif) that degrades APOBEC3 proteins. In vitro APOBEC3F (A3F) anti-HIV-1 activity is weaker than A3G but is partially resistant to Vif degradation unlike A3G. It is unknown whether A3F protein affects HIV-1 disease in vivo. To assess the effect of A3F gene on host susceptibility to HIV- acquisition and disease progression, we performed a genetic association study in six well-characterized HIV-1 natural cohorts. A common six-Single Nucleotide Polymorphism (SNP) haplotype of A3F tagged by a codon-changing variant (p. I231V, with allele (V) frequency of 48% in European Americans) was associated with significantly lower set-point viral load and slower rate of progression to AIDS (Relative Hazards (RH) = 0.71, 95% CI: 0.56, 0.91) and delayed development of pneumocystis pneumonia (PCP) (RH = 0.53, 95% CI: 0.37-0.76). A validation study in the International Collaboration for the Genomics of HIV (ICGH) showed a consistent association with lower set-point viral load. An in vitro assay revealed that the A3F I231V variant may influence Vif mediated A3F degradation. Our results provide genetic epidemiological evidence that A3F modulates HIV-1/AIDS disease progression.


Assuntos
Citosina Desaminase/genética , Infecções por HIV/genética , Pneumonia por Pneumocystis/genética , Produtos do Gene vif do Vírus da Imunodeficiência Humana/genética , Sequência de Aminoácidos , Citosina Desaminase/metabolismo , Progressão da Doença , Infecções por HIV/patologia , Infecções por HIV/virologia , HIV-1/patogenicidade , Haplótipos , Humanos , Pneumonia por Pneumocystis/patologia , Pneumonia por Pneumocystis/virologia , Polimorfismo de Nucleotídeo Único , Ligação Proteica , Produtos do Gene vif do Vírus da Imunodeficiência Humana/metabolismo
12.
Am J Hum Genet ; 97(5): 738-43, 2015 Nov 05.
Artigo em Inglês | MEDLINE | ID: mdl-26456283

RESUMO

The magnitude of the human antibody response to viral antigens is highly variable. To explore the human genetic contribution to this variability, we performed genome-wide association studies of the immunoglobulin G response to 14 pathogenic viruses in 2,363 immunocompetent adults. Significant associations were observed in the major histocompatibility complex region on chromosome 6 for influenza A virus, Epstein-Barr virus, JC polyomavirus, and Merkel cell polyomavirus. Using local imputation and fine mapping, we identified specific amino acid residues in human leucocyte antigen (HLA) class II proteins as the most probable causal variants underlying these association signals. Common HLA-DRß1 haplotypes showed virus-specific patterns of humoral-response regulation. We observed an overlap between variants affecting the humoral response to influenza A and EBV and variants previously associated with autoimmune diseases related to these viruses. The results of this study emphasize the central and pathogen-specific role of HLA class II variation in the modulation of humoral immune response to viral antigens in humans.


Assuntos
Doenças Autoimunes/imunologia , Antígenos de Histocompatibilidade Classe II/genética , Imunidade Humoral/imunologia , Hospedeiro Imunocomprometido/imunologia , Polimorfismo de Nucleotídeo Único/genética , Esquizofrenia/imunologia , Viroses/imunologia , Vírus/imunologia , Adulto , Doenças Autoimunes/genética , Doenças Autoimunes/patologia , Estudos de Casos e Controles , Feminino , Seguimentos , Estudo de Associação Genômica Ampla , Antígenos de Histocompatibilidade Classe II/química , Antígenos de Histocompatibilidade Classe II/imunologia , Humanos , Imunoglobulina G/sangue , Masculino , Prognóstico , Conformação Proteica , Esquizofrenia/genética , Esquizofrenia/patologia , Viroses/genética , Viroses/virologia
13.
PLoS Comput Biol ; 13(2): e1005339, 2017 02.
Artigo em Inglês | MEDLINE | ID: mdl-28182649

RESUMO

We evaluated the fraction of variation in HIV-1 set point viral load attributable to viral or human genetic factors by using joint host/pathogen genetic data from 541 HIV infected individuals. We show that viral genetic diversity explains 29% of the variation in viral load while host factors explain 8.4%. Using a joint model including both host and viral effects, we estimate a total of 30% heritability, indicating that most of the host effects are reflected in viral sequence variation.


Assuntos
Genoma Humano/genética , Genoma Viral/genética , Infecções por HIV/genética , HIV/genética , Modelos Genéticos , Carga Viral/genética , Vacinas contra a AIDS/uso terapêutico , Estudos de Associação Genética/métodos , Predisposição Genética para Doença/genética , Variação Genética/genética , Infecções por HIV/terapia , Interações Hospedeiro-Patógeno/genética , Humanos
14.
Proc Natl Acad Sci U S A ; 112(47): 14658-63, 2015 Nov 24.
Artigo em Inglês | MEDLINE | ID: mdl-26553974

RESUMO

Previous genome-wide association studies (GWAS) of HIV-1-infected populations have been underpowered to detect common variants with moderate impact on disease outcome and have not assessed the phenotypic variance explained by genome-wide additive effects. By combining the majority of available genome-wide genotyping data in HIV-infected populations, we tested for association between ∼8 million variants and viral load (HIV RNA copies per milliliter of plasma) in 6,315 individuals of European ancestry. The strongest signal of association was observed in the HLA class I region that was fully explained by independent effects mapping to five variable amino acid positions in the peptide binding grooves of the HLA-B and HLA-A proteins. We observed a second genome-wide significant association signal in the chemokine (C-C motif) receptor (CCR) gene cluster on chromosome 3. Conditional analysis showed that this signal could not be fully attributed to the known protective CCR5Δ32 allele and the risk P1 haplotype, suggesting further causal variants in this region. Heritability analysis demonstrated that common human genetic variation-mostly in the HLA and CCR5 regions-explains 25% of the variability in viral load. This study suggests that analyses in non-European populations and of variant classes not assessed by GWAS should be priorities for the field going forward.


Assuntos
Predisposição Genética para Doença , HIV-1/genética , Interações Hospedeiro-Patógeno/genética , Polimorfismo de Nucleotídeo Único/genética , Carga Viral/genética , Adulto , Alelos , Aminoácidos/genética , Cromossomos Humanos Par 3/genética , Estudo de Associação Genômica Ampla , Antígenos HLA-B/genética , Humanos , Padrões de Herança/genética , Mapeamento Físico do Cromossomo , Receptores CCR5/genética
15.
J Infect Dis ; 216(9): 1063-1069, 2017 11 27.
Artigo em Inglês | MEDLINE | ID: mdl-28968755

RESUMO

Background: Previous genetic association studies of human immunodeficiency virus-1 (HIV-1) progression have focused on common human genetic variation ascertained through genome-wide genotyping. Methods: We sought to systematically assess the full spectrum of functional variation in protein coding gene regions on HIV-1 progression through exome sequencing of 1327 individuals. Genetic variants were tested individually and in aggregate across genes and gene sets for an influence on HIV-1 viral load. Results: Multiple single variants within the major histocompatibility complex (MHC) region were observed to be strongly associated with HIV-1 outcome, consistent with the known impact of classical HLA alleles. However, no single variant or gene located outside of the MHC region was significantly associated with HIV progression. Set-based association testing focusing on genes identified as being essential for HIV replication in genome-wide small interfering RNA (siRNA) and clustered regularly interspaced short palindromic repeats (CRISPR) studies did not reveal any novel associations. Conclusions: These results suggest that exonic variants with large effect sizes are unlikely to have a major contribution to host control of HIV infection.


Assuntos
Sequenciamento do Exoma , Infecções por HIV/genética , Infecções por HIV/virologia , HIV-1/genética , Interações Hospedeiro-Patógeno/genética , Carga Viral/genética , Adulto , Feminino , Predisposição Genética para Doença , Variação Genética , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único
16.
PLoS Pathog ; 11(6): e1005006, 2015 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-26076473

RESUMO

[This corrects the article DOI: 10.1371/journal.ppat.1003161.].

17.
PLoS Pathog ; 10(5): e1004156, 2014 May.
Artigo em Inglês | MEDLINE | ID: mdl-24875931

RESUMO

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.


Assuntos
Linfócitos T CD4-Positivos/virologia , Infecções por HIV/virologia , HIV-1 , Latência Viral/imunologia , Replicação Viral , Linfócitos T CD4-Positivos/imunologia , Células Cultivadas , Humanos , Modelos Imunológicos , RNA Viral/genética , Integração Viral/genética , Latência Viral/genética
18.
Genet Med ; 18(8): 814-22, 2016 08.
Artigo em Inglês | MEDLINE | ID: mdl-26765343

RESUMO

PURPOSE: The implementation of genomic-based medicine is hindered by unresolved questions regarding data privacy and delivery of interpreted results to health-care practitioners. We used DNA-based prediction of HIV-related outcomes as a model to explore critical issues in clinical genomics. METHODS: We genotyped 4,149 markers in HIV-positive individuals. Variants allowed for prediction of 17 traits relevant to HIV medical care, inference of patient ancestry, and imputation of human leukocyte antigen (HLA) types. Genetic data were processed under a privacy-preserving framework using homomorphic encryption, and clinical reports describing potentially actionable results were delivered to health-care providers. RESULTS: A total of 230 patients were included in the study. We demonstrated the feasibility of encrypting a large number of genetic markers, inferring patient ancestry, computing monogenic and polygenic trait risks, and reporting results under privacy-preserving conditions. The average execution time of a multimarker test on encrypted data was 865 ms on a standard computer. The proportion of tests returning potentially actionable genetic results ranged from 0 to 54%. CONCLUSIONS: The model of implementation presented herein informs on strategies to deliver genomic test results for clinical care. Data encryption to ensure privacy helps to build patient trust, a key requirement on the road to genomic-based medicine.Genet Med 18 8, 814-822.


Assuntos
Segurança Computacional , Privacidade Genética , Infecções por HIV/genética , Variação Genética , Genômica/ética , Humanos , Modelos Teóricos
19.
PLoS Comput Biol ; 11(12): e1004647, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26642228

RESUMO

Sequencing projects have identified large numbers of rare stop-gain and frameshift variants in the human genome. As most of these are observed in the heterozygous state, they test a gene's tolerance to haploinsufficiency and dominant loss of function. We analyzed the distribution of truncating variants across 16,260 autosomal protein coding genes in 11,546 individuals. We observed 39,893 truncating variants affecting 12,062 genes, which significantly differed from an expectation of 12,916 genes under a model of neutral de novo mutation (p<10-4). Extrapolating this to increasing numbers of sequenced individuals, we estimate that 10.8% of human genes do not tolerate heterozygous truncating variants. An additional 10 to 15% of truncated genes may be rescued by incomplete penetrance or compensatory mutations, or because the truncating variants are of limited functional impact. The study of protein truncating variants delineates the essential genome and, more generally, identifies rare heterozygous variants as an unexplored source of diversity of phenotypic traits and diseases.


Assuntos
Mapeamento Cromossômico/métodos , Códon sem Sentido/genética , Variação Genética/genética , Genoma Humano/genética , Proteínas/genética , Sequência de Bases , Humanos , Dados de Sequência Molecular
20.
J Infect Dis ; 212(4): 578-84, 2015 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-25701868

RESUMO

Systemic immune activation, a major determinant of human immunodeficiency virus (HIV) disease progression, is the result of a complex interplay between viral replication, dysregulation of the immune system, and microbial translocation due to gut mucosal damage. Although human genetic variants influencing HIV load have been identified, it is unknown how much the host genetic background contributes to interindividual differences in other determinants of HIV pathogenesis such as gut damage and microbial translocation. Using samples and data from 717 untreated participants in the Swiss HIV Cohort Study and a genome-wide association study design, we searched for human genetic determinants of plasma levels of intestinal fatty acid-binding protein (I-FABP/FABP2), a marker of gut damage, and of soluble CD14 (sCD14), a marker of lipopolysaccharide bioactivity and microbial translocation. We also assessed the correlations between HIV load, sCD14, and I-FABP. Although we found no genome-wide significant determinant of the tested plasma markers, we observed strong associations between sCD14 and both HIV load and I-FABP, shedding new light on the relationships between processes that drive progression of untreated HIV infection.


Assuntos
Fármacos Anti-HIV/administração & dosagem , Predisposição Genética para Doença , Infecções por HIV/genética , Infecções por HIV/virologia , HIV-1/fisiologia , Replicação Viral/fisiologia , Adulto , Fármacos Anti-HIV/uso terapêutico , Biomarcadores/sangue , Estudos de Coortes , Proteínas de Ligação a Ácido Graxo/sangue , Proteínas de Ligação a Ácido Graxo/metabolismo , Feminino , Regulação da Expressão Gênica/fisiologia , Genótipo , Infecções por HIV/epidemiologia , Infecções por HIV/imunologia , Humanos , Receptores de Lipopolissacarídeos/sangue , Receptores de Lipopolissacarídeos/metabolismo , Masculino , Suíça/epidemiologia , Translocação Genética , Carga Viral
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