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1.
J Infect ; 2019 Dec 05.
Artigo em Inglês | MEDLINE | ID: mdl-31812703

RESUMO

OBJECTIVE: Viral fitness plays an important role in HIV-1 evolution, transmission and pathogenesis. However, how mutations accumulated during early infection affect viral fitness has not been well studied. METHODS: Paired infectious molecular clones (IMCs) for transmitted/founder (T/F) and 6-month (6-mo) viruses post infection were generated from 10 infected individuals to investigate the impact of accumulated mutations on viral fitness by comparing 6-mo viruses to their cognate T/F viruses. RESULTS: All ten 6-mo viruses were less fit than their cognate T/F viruses. Moreover, the fitness losses of the 6-mo viruses correlated with the decrease in viral loads from the peak of viremia. CONCLUSION: These results show that the mutations accumulated during half a year post infection collectively reduce viral fitness and thereby contribute to lowering viral loads.

2.
Front Oncol ; 9: 984, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31632915

RESUMO

The application of data science in cancer research has been boosted by major advances in three primary areas: (1) Data: diversity, amount, and availability of biomedical data; (2) Advances in Artificial Intelligence (AI) and Machine Learning (ML) algorithms that enable learning from complex, large-scale data; and (3) Advances in computer architectures allowing unprecedented acceleration of simulation and machine learning algorithms. These advances help build in silico ML models that can provide transformative insights from data including: molecular dynamics simulations, next-generation sequencing, omics, imaging, and unstructured clinical text documents. Unique challenges persist, however, in building ML models related to cancer, including: (1) access, sharing, labeling, and integration of multimodal and multi-institutional data across different cancer types; (2) developing AI models for cancer research capable of scaling on next generation high performance computers; and (3) assessing robustness and reliability in the AI models. In this paper, we review the National Cancer Institute (NCI) -Department of Energy (DOE) collaboration, Joint Design of Advanced Computing Solutions for Cancer (JDACS4C), a multi-institution collaborative effort focused on advancing computing and data technologies to accelerate cancer research on three levels: molecular, cellular, and population. This collaboration integrates various types of generated data, pre-exascale compute resources, and advances in ML models to increase understanding of basic cancer biology, identify promising new treatment options, predict outcomes, and eventually prescribe specialized treatments for patients with cancer.

3.
Philos Trans R Soc Lond B Biol Sci ; 374(1766): 20180142, 2019 02 18.
Artigo em Inglês | MEDLINE | ID: mdl-30966914

RESUMO

Genomic imprinting, where an allele's expression pattern depends on its parental origin, is thought to result primarily from an intragenomic evolutionary conflict. Imprinted genes are widely expressed in the brain and have been linked to various phenotypes, including behaviours related to risk tolerance. In this paper, we analyse a model of evolutionary bet-hedging in a system with imprinted gene expression. Previous analyses of bet-hedging have shown that natural selection may favour alleles and traits that reduce reproductive variance, even at the expense of reducing mean reproductive success, with the trade-off between mean and variance depending on the population size. In species where the sexes have different reproductive variances, this bet-hedging trade-off differs between maternally and paternally inherited alleles. Where males have the higher reproductive variance, alleles are more strongly selected to reduce variance when paternally inherited than when maternally inherited. We connect this result to phenotypes connected with specific imprinted genes, including delay discounting and social dominance. The empirical patterns are consistent with paternally expressed imprinted genes promoting risk-averse behaviours that reduce reproductive variance. Conversely, maternally expressed imprinted genes promote risk-tolerant, variance-increasing behaviours. We indicate how future research might further test the hypotheses suggested by our analysis. This article is part of the theme issue 'Risk taking and impulsive behaviour: fundamental discoveries, theoretical perspectives and clinical implications'.

4.
BMC Bioinformatics ; 19(Suppl 18): 485, 2018 Dec 21.
Artigo em Inglês | MEDLINE | ID: mdl-30577756

RESUMO

BACKGROUND: Manual extraction of information from electronic pathology (epath) reports to populate the Surveillance, Epidemiology, and End Result (SEER) database is labor intensive. Systematizing the data extraction automatically using machine-learning (ML) and natural language processing (NLP) is desirable to reduce the human labor required to populate the SEER database and to improve the timeliness of the data. This enables scaling up registry efficiency and collection of new data elements. To ensure the integrity, quality, and continuity of the SEER data, the misclassification error of ML and NPL algorithms needs to be negligible. Current algorithms fail to achieve the precision of human experts who can bring additional information in their assessments. Differences in registry format and the desire to develop a common information extraction platform further complicate the ML/NLP tasks. The purpose of our study is to develop triage rules to partially automate registry workflow to improve the precision of the auto-extracted information. RESULTS: This paper presents a mathematical framework to improve the precision of a classifier beyond that of the Bayes classifier by selectively classifying item that are most likely to be correct. This results in a triage rule that only classifies a subset of the item. We characterize the optimal triage rule and demonstrate its usefulness in the problem of classifying cancer site from electronic pathology reports to achieve a desired precision. CONCLUSIONS: From the mathematical formalism, we propose a heuristic estimate for triage rule based on post-processing the soft-max output from standard machine learning algorithms. We show, in test cases, that the triage rule significantly improve the classification accuracy.


Assuntos
Computadores/tendências , Bases de Dados Factuais/tendências , Triagem/métodos , Teorema de Bayes , Humanos , Armazenamento e Recuperação da Informação
5.
Proc Natl Acad Sci U S A ; 115(30): E7139-E7148, 2018 07 24.
Artigo em Inglês | MEDLINE | ID: mdl-29987026

RESUMO

RNA viruses exist as a genetically diverse quasispecies with extraordinary ability to adapt to abrupt changes in the host environment. However, the molecular mechanisms that contribute to their rapid adaptation and persistence in vivo are not well studied. Here, we probe hepatitis C virus (HCV) persistence by analyzing clinical samples taken from subjects who were treated with a second-generation HCV protease inhibitor. Frequent longitudinal viral load determinations and large-scale single-genome sequence analyses revealed rapid antiviral resistance development, and surprisingly, dynamic turnover of dominant drug-resistant mutant populations long after treatment cessation. We fitted mathematical models to both the viral load and the viral sequencing data, and the results provided strong support for the critical roles that superinfection and cure of infected cells play in facilitating the rapid turnover and persistence of viral populations. More broadly, our results highlight the importance of considering viral dynamics and competition at the intracellular level in understanding rapid viral adaptation. Thus, we propose a theoretical framework integrating viral and molecular mechanisms to explain rapid viral evolution, resistance, and persistence despite antiviral treatment and host immune responses.


Assuntos
Adaptação Fisiológica , Antivirais/uso terapêutico , Farmacorresistência Viral , Hepacivirus , Hepatite C , Modelos Biológicos , Adaptação Fisiológica/efeitos dos fármacos , Adaptação Fisiológica/genética , Farmacorresistência Viral/efeitos dos fármacos , Farmacorresistência Viral/genética , Hepacivirus/genética , Hepacivirus/metabolismo , Hepatite C/tratamento farmacológico , Hepatite C/genética , Hepatite C/metabolismo , Humanos
6.
Nat Commun ; 9(1): 1928, 2018 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-29765018

RESUMO

Recombination in HIV-1 is well documented, but its importance in the low-diversity setting of within-host diversification is less understood. Here we develop a novel computational tool (RAPR (Recombination Analysis PRogram)) to enable a detailed view of in vivo viral recombination during early infection, and we apply it to near-full-length HIV-1 genome sequences from longitudinal samples. Recombinant genomes rapidly replace transmitted/founder (T/F) lineages, with a median half-time of 27 days, increasing the genetic complexity of the viral population. We identify recombination hot and cold spots that differ from those observed in inter-subtype recombinants. Furthermore, RAPR analysis of longitudinal samples from an individual with well-characterized neutralizing antibody responses shows that recombination helps carry forward resistance-conferring mutations in the diversifying quasispecies. These findings provide insight into molecular mechanisms by which viral recombination contributes to HIV-1 persistence and immunopathogenesis and have implications for studies of HIV transmission and evolution in vivo.


Assuntos
Evolução Molecular , Infecções por HIV/virologia , HIV-1/genética , Recombinação Genética , Variação Genética , Genótipo , HIV-1/classificação , HIV-1/isolamento & purificação , Humanos , Estudos Longitudinais , Masculino , Filogenia
7.
Proc Natl Acad Sci U S A ; 114(49): 12910-12915, 2017 12 05.
Artigo em Inglês | MEDLINE | ID: mdl-29158378

RESUMO

Languages are transmitted through channels created by kinship systems. Given sufficient time, these kinship channels can change the genetic and linguistic structure of populations. In traditional societies of eastern Indonesia, finely resolved cophylogenies of languages and genes reveal persistent movements between stable speech communities facilitated by kinship rules. When multiple languages are present in a region and postmarital residence rules encourage sustained directional movement between speech communities, then languages should be channeled along uniparental lines. We find strong evidence for this pattern in 982 individuals from 25 villages on two adjacent islands, where different kinship rules have been followed. Core groups of close relatives have stayed together for generations, while remaining in contact with, and marrying into, surrounding groups. Over time, these kinship systems shaped their gene and language phylogenies: Consistently following a postmarital residence rule turned social communities into speech communities.


Assuntos
Linguagem , DNA Mitocondrial/genética , Família , Feminino , Variação Genética , Migração Humana , Humanos , Indonésia , Ilhas , Linguística , Masculino , Filogenia , Análise de Sequência de DNA
8.
Retrovirology ; 14(1): 46, 2017 Oct 10.
Artigo em Inglês | MEDLINE | ID: mdl-29017536

RESUMO

BACKGROUND: Mutations rapidly accumulate in the HIV-1 genome after infection. Some of those mutations are selected by host immune responses and often cause viral fitness losses. This study is to investigate whether strongly selected mutations that are not associated with immune responses result in fitness losses. RESULTS: Strongly selected mutations were identified by analyzing 5'-half HIV-1 genome (gag/pol) sequences from longitudinal samples of subject CH0131. The K43R mutation in the gag gene was first detected at day 91 post screening and was fixed in the viral population at day 273 while the synonymous N323tc mutation was first detected at day 177 and fixed at day 670. No conventional or cryptic T cell responses were detected against either mutation sites by ELISpot analysis. However, when fitness costs of both mutations were measured by introducing each mutation into their cognate transmitted/founder (T/F) viral genome, the K43R mutation caused a significant fitness loss while the N323tc mutation had little impact on viral fitness. CONCLUSIONS: The rapid fixation, the lack of detectable immune responses and the significant fitness cost of the K43R mutation suggests that it was strongly selected by host factors other than T cell responses and neutralizing antibodies.


Assuntos
Anticorpos Neutralizantes/imunologia , Linfócitos T CD8-Positivos/imunologia , Genoma Viral/genética , Infecções por HIV/imunologia , HIV-1/genética , Produtos do Gene gag do Vírus da Imunodeficiência Humana/genética , Técnicas de Cultura de Células , ELISPOT , Epitopos de Linfócito T/imunologia , Aptidão Genética/genética , Infecções por HIV/virologia , HIV-1/imunologia , Humanos , Evasão da Resposta Imune/genética , Mutação , Seleção Genética/genética , Replicação Viral , Produtos do Gene gag do Vírus da Imunodeficiência Humana/imunologia
9.
Astrobiology ; 17(3): 266-276, 2017 03.
Artigo em Inglês | MEDLINE | ID: mdl-28323481

RESUMO

It is well known that life on Earth alters its environment over evolutionary and geological timescales. An important open question is whether this is a result of evolutionary optimization or a universal feature of life. In the latter case, the origin of life would be coincident with a shift in environmental conditions. Here we present a model for the emergence of life in which replicators are explicitly coupled to their environment through the recycling of a finite supply of resources. The model exhibits a dynamic, first-order phase transition from nonlife to life, where the life phase is distinguished by selection on replicators. We show that environmental coupling plays an important role in the dynamics of the transition. The transition corresponds to a redistribution of matter in replicators and their environment, driven by selection on replicators, exhibiting an explosive growth in diversity as replicators are selected. The transition is accurately tracked by the mutual information shared between replicators and their environment. In the absence of successfully repartitioning system resources, the transition fails to complete, leading to the possibility of many frustrated trials before life first emerges. Often, the replicators that initiate the transition are not those that are ultimately selected. The results are consistent with the view that life's propensity to shape its environment is indeed a universal feature of replicators, characteristic of the transition from nonlife to life. We discuss the implications of these results for understanding life's emergence and evolutionary transitions more broadly. Key Words: Origin of life-Prebiotic evolution-Astrobiology-Biopolymers-Life. Astrobiology 17, 266-276.


Assuntos
Origem da Vida , Transição de Fase , Fatores de Tempo
10.
Sci Rep ; 6: 38130, 2016 12 02.
Artigo em Inglês | MEDLINE | ID: mdl-27909304

RESUMO

A severe bottleneck exists during HIV-1 mucosal transmission. However, viral properties that determine HIV-1 transmissibility are not fully elucidated. We identified multiple transmitted/founder (T/F) viruses in six HIV-1-infected subjects by analyzing whole genome sequences. Comparison of biological phenotypes of different T/F viruses from the same individual allowed us to more precisely identify critical determinants for viral transmissibility since they were transmitted under similar conditions. All T/F viruses used coreceptor CCR5, while no T/F viruses used CXCR4 or GPR15. However, the efficiency for different T/F viruses from the same individual to use CCR5 was significantly variable, and the differences were even more significant for usage of coreceptors FPRL1, CCR3 and APJ. Resistance to IFN-α was also different between T/F viruses in 2 of 3 individuals. The relative fitness between T/F viruses from the same subject was highly variable (2-6%). Importantly, the levels of coreceptor usage efficiency, resistance to IFN-α and viral fitness were not associated with proportions of T/F viruses in each individual during acute infection. Our results show that the modest but significant differences in coreceptor usage efficiency, IFN-α sensitivity and viral fitness each alone may not play a critical role in HIV-1 transmission.


Assuntos
Infecções por HIV/virologia , HIV-1/classificação , HIV-1/genética , Variação Genética , Genoma Viral , Infecções por HIV/transmissão , HIV-1/fisiologia , Humanos , Interferon-alfa/farmacologia , Masculino , Fenótipo , Receptores CCR5/fisiologia , Receptores de HIV/fisiologia , Tropismo Viral/genética , Replicação Viral/efeitos dos fármacos
11.
PLoS Pathog ; 12(3): e1005520, 2016 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-27028935

RESUMO

The identification of a new generation of potent broadly neutralizing HIV-1 antibodies (bnAbs) has generated substantial interest in their potential use for the prevention and/or treatment of HIV-1 infection. While combinations of bnAbs targeting distinct epitopes on the viral envelope (Env) will likely be required to overcome the extraordinary diversity of HIV-1, a key outstanding question is which bnAbs, and how many, will be needed to achieve optimal clinical benefit. We assessed the neutralizing activity of 15 bnAbs targeting four distinct epitopes of Env, including the CD4-binding site (CD4bs), the V1/V2-glycan region, the V3-glycan region, and the gp41 membrane proximal external region (MPER), against a panel of 200 acute/early clade C HIV-1 Env pseudoviruses. A mathematical model was developed that predicted neutralization by a subset of experimentally evaluated bnAb combinations with high accuracy. Using this model, we performed a comprehensive and systematic comparison of the predicted neutralizing activity of over 1,600 possible double, triple, and quadruple bnAb combinations. The most promising bnAb combinations were identified based not only on breadth and potency of neutralization, but also other relevant measures, such as the extent of complete neutralization and instantaneous inhibitory potential (IIP). By this set of criteria, triple and quadruple combinations of bnAbs were identified that were significantly more effective than the best double combinations, and further improved the probability of having multiple bnAbs simultaneously active against a given virus, a requirement that may be critical for countering escape in vivo. These results provide a rationale for advancing bnAb combinations with the best in vitro predictors of success into clinical trials for both the prevention and treatment of HIV-1 infection.


Assuntos
Anticorpos Neutralizantes/imunologia , Anticorpos Anti-HIV/imunologia , Infecções por HIV/prevenção & controle , HIV-1/imunologia , Epitopos/imunologia , Infecções por HIV/imunologia , Humanos
12.
Proc Natl Acad Sci U S A ; 113(7): 1766-71, 2016 Feb 16.
Artigo em Inglês | MEDLINE | ID: mdl-26831113

RESUMO

How universal is human conceptual structure? The way concepts are organized in the human brain may reflect distinct features of cultural, historical, and environmental background in addition to properties universal to human cognition. Semantics, or meaning expressed through language, provides indirect access to the underlying conceptual structure, but meaning is notoriously difficult to measure, let alone parameterize. Here, we provide an empirical measure of semantic proximity between concepts using cross-linguistic dictionaries to translate words to and from languages carefully selected to be representative of worldwide diversity. These translations reveal cases where a particular language uses a single "polysemous" word to express multiple concepts that another language represents using distinct words. We use the frequency of such polysemies linking two concepts as a measure of their semantic proximity and represent the pattern of these linkages by a weighted network. This network is highly structured: Certain concepts are far more prone to polysemy than others, and naturally interpretable clusters of closely related concepts emerge. Statistical analysis of the polysemies observed in a subset of the basic vocabulary shows that these structural properties are consistent across different language groups, and largely independent of geography, environment, and the presence or absence of a literary tradition. The methods developed here can be applied to any semantic domain to reveal the extent to which its conceptual structure is, similarly, a universal attribute of human cognition and language use.


Assuntos
Semântica , Humanos
13.
J Virol ; 90(1): 152-66, 2016 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-26468546

RESUMO

UNLABELLED: Despite the recent development of highly effective anti-hepatitis C virus (HCV) drugs, the global burden of this pathogen remains immense. Control or eradication of HCV will likely require the broad application of antiviral drugs and development of an effective vaccine. A precise molecular identification of transmitted/founder (T/F) HCV genomes that lead to productive clinical infection could play a critical role in vaccine research, as it has for HIV-1. However, the replication schema of these two RNA viruses differ substantially, as do viral responses to innate and adaptive host defenses. These differences raise questions as to the certainty of T/F HCV genome inferences, particularly in cases where multiple closely related sequence lineages have been observed. To clarify these issues and distinguish between competing models of early HCV diversification, we examined seven cases of acute HCV infection in humans and chimpanzees, including three examples of virus transmission between linked donors and recipients. Using single-genome sequencing (SGS) of plasma vRNA, we found that inferred T/F sequences in recipients were identical to viral sequences in their respective donors. Early in infection, HCV genomes generally evolved according to a simple model of random evolution where the coalescent corresponded to the T/F sequence. Closely related sequence lineages could be explained by high multiplicity infection from a donor whose viral sequences had undergone a pretransmission bottleneck due to treatment, immune selection, or recent infection. These findings validate SGS, together with mathematical modeling and phylogenetic analysis, as a novel strategy to infer T/F HCV genome sequences. IMPORTANCE: Despite the recent development of highly effective, interferon-sparing anti-hepatitis C virus (HCV) drugs, the global burden of this pathogen remains immense. Control or eradication of HCV will likely require the broad application of antiviral drugs and the development of an effective vaccine, which could be facilitated by a precise molecular identification of transmitted/founder (T/F) viral genomes and their progeny. We used single-genome sequencing to show that inferred HCV T/F sequences in recipients were identical to viral sequences in their respective donors and that viral genomes generally evolved early in infection according to a simple model of random sequence evolution. Altogether, the findings validate T/F genome inferences and illustrate how T/F sequence identification can illuminate studies of HCV transmission, immunopathogenesis, drug resistance development, and vaccine protection, including sieving effects on breakthrough virus strains.


Assuntos
Variação Genética , Hepacivirus/classificação , Hepacivirus/genética , Hepatite C/transmissão , Transplante de Fígado/efeitos adversos , Doadores de Tecidos , Transplantados , Animais , Análise por Conglomerados , Genoma Viral , Genótipo , Técnicas de Genotipagem , Hepacivirus/isolamento & purificação , Hepatite C/veterinária , Hepatite C/virologia , Humanos , Modelos Teóricos , Dados de Sequência Molecular , Pan troglodytes , Filogenia , Análise de Sequência de DNA , Homologia de Sequência
14.
Phys Rev Lett ; 115(21): 212002, 2015 Nov 20.
Artigo em Inglês | MEDLINE | ID: mdl-26636847

RESUMO

We present lattice QCD results on the neutron tensor charges including, for the first time, a simultaneous extrapolation in the lattice spacing, volume, and light quark masses to the physical point in the continuum limit. We find that the "disconnected" contribution is smaller than the statistical error in the "connected" contribution. Our estimates in the modified minimal subtraction scheme at 2 GeV, including all systematics, are g_{T}^{d-u}=1.020(76), g_{T}^{d}=0.774(66), g_{T}^{u}=-0.233(28), and g_{T}^{s}=0.008(9). The flavor diagonal charges determine the size of the neutron electric dipole moment (EDM) induced by quark EDMs that are generated in many new scenarios of CP violation beyond the standard model. We use our results to derive model-independent bounds on the EDMs of light quarks and update the EDM phenomenology in split supersymmetry with gaugino mass unification, finding a stringent upper bound of d_{n}<4×10^{-28} e cm for the neutron EDM in this scenario.


Assuntos
Modelos Teóricos , Nêutrons , Partículas Elementares , Física Nuclear , Termodinâmica
15.
Viruses ; 7(10): 5443-75, 2015 Oct 21.
Artigo em Inglês | MEDLINE | ID: mdl-26506369

RESUMO

Within-host genetic sequencing from samples collected over time provides a dynamic view of how viruses evade host immunity. Immune-driven mutations might stimulate neutralization breadth by selecting antibodies adapted to cycles of immune escape that generate within-subject epitope diversity. Comprehensive identification of immune-escape mutations is experimentally and computationally challenging. With current technology, many more viral sequences can readily be obtained than can be tested for binding and neutralization, making down-selection necessary. Typically, this is done manually, by picking variants that represent different time-points and branches on a phylogenetic tree. Such strategies are likely to miss many relevant mutations and combinations of mutations, and to be redundant for other mutations. Longitudinal Antigenic Sequences and Sites from Intrahost Evolution (LASSIE) uses transmitted founder loss to identify virus "hot-spots" under putative immune selection and chooses sequences that represent recurrent mutations in selected sites. LASSIE favors earliest sequences in which mutations arise. With well-characterized longitudinal Env sequences, we confirmed selected sites were concentrated in antibody contacts and selected sequences represented diverse antigenic phenotypes. Practical applications include rapidly identifying immune targets under selective pressure within a subject, selecting minimal sets of reagents for immunological assays that characterize evolving antibody responses, and for immunogens in polyvalent "cocktail" vaccines.


Assuntos
Antígenos Virais/imunologia , Infecções por HIV/imunologia , Infecções por HIV/virologia , HIV/imunologia , Evasão da Resposta Imune , Seleção Genética , Virologia/métodos , Antígenos Virais/genética , Variação Genética , HIV/classificação , HIV/genética , HIV/isolamento & purificação , Humanos , Estudos Longitudinais
16.
Curr Biol ; 25(1): 1-9, 2015 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-25532895

RESUMO

BACKGROUND: Concerted evolution is normally used to describe parallel changes at different sites in a genome, but it is also observed in languages where a specific phoneme changes to the same other phoneme in many words in the lexicon­a phenomenon known as regular sound change. We develop a general statistical model that can detect concerted changes in aligned sequence data and apply it to study regular sound changes in the Turkic language family. RESULTS: Linguistic evolution, unlike the genetic substitutional process, is dominated by events of concerted evolutionary change. Our model identified more than 70 historical events of regular sound change that occurred throughout the evolution of the Turkic language family, while simultaneously inferring a dated phylogenetic tree. Including regular sound changes yielded an approximately 4-fold improvement in the characterization of linguistic change over a simpler model of sporadic change, improved phylogenetic inference, and returned more reliable and plausible dates for events on the phylogenies. The historical timings of the concerted changes closely follow a Poisson process model, and the sound transition networks derived from our model mirror linguistic expectations. CONCLUSIONS: We demonstrate that a model with no prior knowledge of complex concerted or regular changes can nevertheless infer the historical timings and genealogical placements of events of concerted change from the signals left in contemporary data. Our model can be applied wherever discrete elements­such as genes, words, cultural trends, technologies, or morphological traits­can change in parallel within an organism or other evolving group.


Assuntos
Evolução Cultural , Fonética , Humanos , Modelos Estatísticos , Filogenia
17.
Retrovirology ; 11: 101, 2014 Nov 19.
Artigo em Inglês | MEDLINE | ID: mdl-25407514

RESUMO

BACKGROUND: Fitness costs and slower disease progression are associated with a cytolytic T lymphocyte (CTL) escape mutation T242N in Gag in HIV-1-infected individuals carrying HLA-B*57/5801 alleles. However, the impact of different context in diverse HIV-1 strains on the fitness costs due to the T242N mutation has not been well characterized. To better understand the extent of fitness costs of the T242N mutation and the repair of fitness loss through compensatory amino acids, we investigated its fitness impact in different transmitted/founder (T/F) viruses. RESULTS: The T242N mutation resulted in various levels of fitness loss in four different T/F viruses. However, the fitness costs were significantly compromised by preexisting compensatory amino acids in (Isoleucine at position 247) or outside (glutamine at position 219) the CTL epitope. Moreover, the transmitted T242N escape mutant in subject CH131 was as fit as the revertant N242T mutant and the elimination of the compensatory amino acid I247 in the T/F viral genome resulted in significant fitness cost, suggesting the fitness loss caused by the T242N mutation had been fully repaired in the donor at transmission. Analysis of the global circulating HIV-1 sequences in the Los Alamos HIV Sequence Database showed a high prevalence of compensatory amino acids for the T242N mutation and other T cell escape mutations. CONCLUSIONS: Our results show that the preexisting compensatory amino acids in the majority of circulating HIV-1 strains could significantly compromise the fitness loss due to CTL escape mutations and thus increase challenges for T cell based vaccines.


Assuntos
HIV-1/imunologia , HIV-1/fisiologia , Evasão da Resposta Imune , Mutação de Sentido Incorreto , Linfócitos T/imunologia , Replicação Viral , Aminoácidos/genética , HIV-1/genética , Humanos , Produtos do Gene gag do Vírus da Imunodeficiência Humana/genética , Produtos do Gene gag do Vírus da Imunodeficiência Humana/imunologia , Produtos do Gene gag do Vírus da Imunodeficiência Humana/metabolismo
18.
Phys Rev Lett ; 113(8): 082001, 2014 Aug 22.
Artigo em Inglês | MEDLINE | ID: mdl-25192088

RESUMO

We report on the first lattice calculation of the QCD phase transition using chiral fermions with physical quark masses. This calculation uses 2+1 quark flavors, spatial volumes between (4 fm)(3) and (11 fm)(3) and temperatures between 139 and 196 MeV. Each temperature is calculated at a single lattice spacing corresponding to a temporal Euclidean extent of N(t) = 8. The disconnected chiral susceptibility, χ(disc) shows a pronounced peak whose position and height depend sensitively on the quark mass. We find no metastability near the peak and a peak height which does not change when a 5 fm spatial extent is increased to 10 fm. Each result is strong evidence that the QCD "phase transition" is not first order but a continuous crossover for m(π) = 135 MeV. The peak location determines a pseudocritical temperature T(c) = 155(1)(8) MeV, in agreement with earlier staggered fermion results. However, the peak height is 50% greater than that suggested by previous staggered results. Chiral SU(2)(L) × SU(2)(R) symmetry is fully restored above 164 MeV, but anomalous U(1)(A) symmetry breaking is nonzero above T(c) and vanishes as T is increased to 196 MeV.

19.
PLoS Pathog ; 10(7): e1004281, 2014 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-25080100

RESUMO

Human APOBEC3 proteins are cytidine deaminases that contribute broadly to innate immunity through the control of exogenous retrovirus replication and endogenous retroelement retrotransposition. As an intrinsic antiretroviral defense mechanism, APOBEC3 proteins induce extensive guanosine-to-adenosine (G-to-A) mutagenesis and inhibit synthesis of nascent human immunodeficiency virus-type 1 (HIV-1) cDNA. Human APOBEC3 proteins have additionally been proposed to induce infrequent, potentially non-lethal G-to-A mutations that make subtle contributions to sequence diversification of the viral genome and adaptation though acquisition of beneficial mutations. Using single-cycle HIV-1 infections in culture and highly parallel DNA sequencing, we defined trinucleotide contexts of the edited sites for APOBEC3D, APOBEC3F, APOBEC3G, and APOBEC3H. We then compared these APOBEC3 editing contexts with the patterns of G-to-A mutations in HIV-1 DNA in cells obtained sequentially from ten patients with primary HIV-1 infection. Viral substitutions were highest in the preferred trinucleotide contexts of the edited sites for the APOBEC3 deaminases. Consistent with the effects of immune selection, amino acid changes accumulated at the APOBEC3 editing contexts located within human leukocyte antigen (HLA)-appropriate epitopes that are known or predicted to enable peptide binding. Thus, APOBEC3 activity may induce mutations that influence the genetic diversity and adaptation of the HIV-1 population in natural infection.


Assuntos
Adaptação Fisiológica/genética , Evolução Biológica , Citosina Desaminase/genética , Variação Genética/genética , Infecções por HIV/virologia , HIV-1/genética , Mutação/genética , Desaminase APOBEC-3G , Aminoidrolases/genética , Sequência de Bases , Citidina Desaminase/genética , DNA Viral/genética , Genoma Viral , Infecções por HIV/genética , Infecções por HIV/imunologia , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Dados de Sequência Molecular , Filogenia , Reação em Cadeia da Polimerase , Homologia de Sequência do Ácido Nucleico , Replicação Viral/genética
20.
J Virol ; 88(21): 12623-43, 2014 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-25142591

RESUMO

UNLABELLED: Neutralizing antibodies (nAbs) are a high priority for vaccines that aim to prevent the acquisition of HIV-1 infection. Vaccine effectiveness will depend on the extent to which induced antibodies neutralize the global diversity of circulating HIV-1 variants. Using large panels of genetically and geographically diverse HIV-1 Env-pseudotyped viruses and chronic infection plasma samples, we unambiguously show that cross-clade nAb responses are commonly induced in response to infection by any virus clade. Nonetheless, neutralization was significantly greater when the plasma clade matched the clade of the virus being tested. This within-clade advantage was diminished in older, more-diverse epidemics in southern Africa, the United States, and Europe compared to more recent epidemics in Asia. It was most pronounced for circulating recombinant form (CRF) 07_BC, which is common in China and is the least-divergent lineage studied; this was followed by the slightly more diverse Asian CRF01_AE. We found no evidence that transmitted/founder viruses are generally more susceptible to neutralization and are therefore easier targets for vaccination than chronic viruses. Features of the gp120 V1V2 loop, in particular, length, net charge, and number of N-linked glycans, were associated with Env susceptibility and plasma neutralization potency in a manner consistent with neutralization escape being a force that drives viral diversification and plasma neutralization breadth. The overall susceptibility of Envs and potencies of plasma samples were highly predictive of the neutralization outcome of any single virus-plasma combination. These findings highlight important considerations for the design and testing of candidate HIV-1 vaccines that aim to elicit effective nAbs. IMPORTANCE: An effective HIV-1 vaccine will need to overcome the extraordinary variability of the virus, which is most pronounced in the envelope glycoproteins (Env), which are the sole targets for neutralizing antibodies (nAbs). Distinct genetic lineages, or clades, of HIV-1 occur in different locales that may require special consideration when designing and testing vaccines candidates. We show that nAb responses to HIV-1 infection are generally active across clades but are most potent within clades. Because effective vaccine-induced nAbs are likely to share these properties, optimal coverage of a particular clade or combination of clades may require clade-matched immunogens. Optimal within-clade coverage might be easier to achieve in regions such as China and Thailand, where the epidemic is more recent and the virus less diverse than in southern Africa, the United States, and Europe. Finally, features of the first and second hypervariable regions of gp120 (V1V2) may be critical for optimal vaccine design.


Assuntos
Anticorpos Neutralizantes/sangue , Epidemias , Anticorpos Anti-HIV/sangue , Infecções por HIV/epidemiologia , Infecções por HIV/imunologia , HIV-1/imunologia , Produtos do Gene env do Vírus da Imunodeficiência Humana/imunologia , Genótipo , Geografia , Saúde Global , Infecções por HIV/virologia , HIV-1/classificação , HIV-1/genética , HIV-1/isolamento & purificação , Humanos , Fatores de Tempo , Produtos do Gene env do Vírus da Imunodeficiência Humana/genética
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