Long-term intrapatient evolution during HIV-2 infection
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ABSTRACT:
SUBMITTER: MacNeil A
PROVIDER: S-EPMC1716858 | biostudies-literature | 2006 Jan
REPOSITORIES: biostudies-literature
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Project description:Many microbial populations rapidly adapt to changing environments with multiple variants competing for survival. To quantify such complex evolutionary dynamics in vivo, time resolved and genome wide data including rare variants are essential. We performed whole-genome deep sequencing of HIV-1 populations in 9 untreated patients, with 6-12 longitudinal samples per patient spanning 5-8 years of infection. The data can be accessed and explored via an interactive web application. We show that patterns of minor diversity are reproducible between patients and mirror global HIV-1 diversity, suggesting a universal landscape of fitness costs that control diversity. Reversions towards the ancestral HIV-1 sequence are observed throughout infection and account for almost one third of all sequence changes. Reversion rates depend strongly on conservation. Frequent recombination limits linkage disequilibrium to about 100 bp in most of the genome, but strong hitch-hiking due to short range linkage limits diversity.
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Project description:We used microarrays to study the evolution of gene expression in two bacterial ecotypes that coexisted for more than 35000 generations of experimental evolution in an extremely simple environment We sampled four clones from each of two lineages at generations 6,500, 17,000 and 40,000 from the polymorphic Ara-2 population of the E. coli long-term evolution experiment. The four clones from each lineage and generation were mixed equally and used for global expression profiling, growth assays and competition experiments. Global expression profiles and growth assays were also performed on the ancestral strain. RNA extractions were done using cells in mid-exponential growth in the same glucose-limited minimal medium used in the evolution experiment. Global expression profiles were obtained by using Affymetrix arrays, with 5 or 6 biological replicates for each lineage-generation sample.
2012-01-01 | E-GEOD-30639 | biostudies-arrayexpress
Project description:One of the most intriguing puzzles in biology is the degree to which evolution is repeatable. The repeatability of evolution, or parallel evolution, has been studied in a variety of model systems, but has rarely been investigated with clinically relevant viruses. To investigate parallel evolution of HIV-1, we passaged two replicate HIV-1 populations for almost 1 year in each of two human T-cell lines. For each of the four evolution lines, we determined the genetic composition of the viral population at nine time points by deep sequencing the entire genome. Mutations that were carried by the majority of the viral population accumulated continuously over 1 year in each evolution line. Many majority mutations appeared in more than one evolution line, that is, our experiments showed an extreme degree of parallel evolution. In one of the evolution lines, 62% of the majority mutations also occur in another line. The parallelism impairs our ability to reconstruct the evolutionary history by phylogenetic methods. We show that one can infer the correct phylogenetic topology by including minority mutations in our analysis. We also find that mutation diversity at the beginning of the experiment is predictive of the frequency of majority mutations at the end of the experiment.
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Project description:ObjectiveOne of the most disabling aspects of living with chronic epilepsy is the unpredictability of seizures. Cumulative research in the past decades has advanced our understanding of the dynamics of seizure risk. Technological advances have recently made it possible to record pertinent biological signals, including electroencephalogram (EEG), continuously. We aimed to assess whether patient-specific seizure forecasting is possible using remote, minimally invasive ultra-long-term subcutaneous EEG.MethodsWe analyzed a two-center cohort of ultra-long-term subcutaneous EEG recordings, including six patients with drug-resistant focal epilepsy monitored for 46-230 days with median 18 h/day of recorded data, totaling >11 000 h of EEG. Total electrographic seizures identified by visual review ranged from 12 to 36 per patient. Three candidate subject-specific long short-term memory network deep learning classifiers were trained offline and pseudoprospectively on preictal (1 h before) and interictal (>1 day from seizures) EEG segments. Performance was assessed relative to a random predictor. Periodicity of the final forecasts was also investigated with autocorrelation.ResultsDepending on each architecture, significant forecasting performance was achieved in three to five of six patients, with overall mean area under the receiver operating characteristic curve of .65-.74. Significant forecasts showed sensitivity ranging from 64% to 80% and time in warning from 10.9% to 44.4%. Overall, the output of the forecasts closely followed patient-specific circadian patterns of seizure occurrence.SignificanceThis study demonstrates proof-of-principle for the possibility of subject-specific seizure forecasting using a minimally invasive subcutaneous EEG device capable of ultra-long-term at-home recordings. These results are encouraging for the development of a prospective seizure forecasting trial with minimally invasive EEG.
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Project description:We used microarrays to study the evolution of gene expression in two bacterial ecotypes that coexisted for more than 35000 generations of experimental evolution in an extremely simple environment
2012-01-01 | GSE30639 | GEO
Project description:ObjectiveTo inform guidelines concerning when to initiate combination antiretroviral therapy (ART), we investigated whether CD4(+) T-cell counts (CD4 cell counts) continue to increase over long periods of time on ART. Losses-to-follow-up and some patients discontinuing ART at higher CD4 cell counts hamper such evaluation, but novel statistical methods can help address these issues. We estimated the long-term CD4 cell count trajectory accounting for losses-to-follow-up and treatment discontinuations.DesignThe study population included 898 US patients first initiating ART in a randomized trial (AIDS Clinical Trials Group 384); 575 were subsequently prospectively followed in an observational study (AIDS Clinical Trials Group Longitudinal Linked Randomized Trials).MethodsInverse probability of censoring weighting statistical methods were used to estimate the CD4 cell count trajectory accounting for losses-to-follow-up and ART discontinuations, overall and for pretreatment CD4 cell count categories (<or=200, 201-350, 351-500, and >500 cells/microl).ResultsMedian CD4 cell count increased from 270 cells/microl pre-ART to an estimated 556 cells/microl at 3 and 532 cells/microl at 7 years after starting ART in analyses ignoring treatment discontinuations, and to 570 and 640 cells/microl, respectively, had all patients continued ART. However, even had ART been continued, an estimated 25, 9, 3, and 2% of patients with pretreatment CD4 cell counts of 200 or less, 201-350, 351-500, and more than 500 cells/microl would have had CD4 cell counts of 350 cells/microl or less after 7 years.ConclusionIf patients remain on ART, CD4 cell counts increase in most patients for at least 7 years. However, the substantial percentage of patients starting therapy at low CD4 cell counts who still had low CD4 cell counts after 7 years provides support for ART initiation at higher CD4 cell counts.
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Project description:Burkholderia multivorans is an opportunistic pathogen capable of causing severe disease in patients with cystic fibrosis (CF). Patients may be chronically infected for years, during which the bacterial population evolves in response to unknown forces. Here we analyze the genomic and functional evolution of a B. multivorans infection that was sequentially sampled from a CF patient over 20 years. The population diversified into at least four primary, coexisting clades with distinct evolutionary dynamics. The average substitution rate was only 2.4 mutations/year, but notably, some lineages evolved more slowly, whereas one diversified more rapidly by mostly nonsynonymous mutations. Ten loci, mostly involved in gene expression regulation and lipid metabolism, acquired three or more independent mutations and define likely targets of selection. Further, a broad range of phenotypes changed in association with the evolved mutations; they included antimicrobial resistance, biofilm regulation, and the presentation of lipopolysaccharide O-antigen repeats, which was directly caused by evolved mutations. Additionally, early isolates acquired mutations in genes involved in cyclic di-GMP (c-di-GMP) metabolism that associated with increased c-di-GMP intracellular levels. Accordingly, these isolates showed lower motility and increased biofilm formation and adhesion to CFBE41o- epithelial cells than the initial isolate, and each of these phenotypes is an important trait for bacterial persistence. The timing of the emergence of this clade of more adherent genotypes correlated with the period of greatest decline in the patient's lung function. All together, our observations suggest that selection on B. multivorans populations during long-term colonization of CF patient lungs either directly or indirectly targets adherence, metabolism, and changes in the cell envelope related to adaptation to the biofilm lifestyle. IMPORTANCE Bacteria may become genetically and phenotypically diverse during long-term colonization of cystic fibrosis (CF) patient lungs, yet our understanding of within-host evolutionary processes during these infections is lacking. Here we combined current genome sequencing technologies and detailed phenotypic profiling of the opportunistic pathogen Burkholderia multivorans using sequential isolates sampled from a CF patient over 20 years. The evolutionary history of these isolates highlighted bacterial genes and pathways that were likely subject to strong selection within the host and were associated with altered phenotypes, such as biofilm production, motility, and antimicrobial resistance. Importantly, multiple lineages coexisted for years or even decades within the infection, and the period of diversification within the dominant lineage was associated with deterioration of the patient's lung function. Identifying traits under strong selection during chronic infection not only sheds new light onto Burkholderia evolution but also sets the stage for tailored therapeutics targeting the prevailing lineages associated with disease progression.
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