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1.
PLoS Negl Trop Dis ; 13(5): e0007231, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-31067235

RESUMO

In recent years, an increasing number of outbreaks of Dengue, Chikungunya and Zika viruses have been reported in Asia and the Americas. Monitoring virus genotype diversity is crucial to understand the emergence and spread of outbreaks, both aspects that are vital to develop effective prevention and treatment strategies. Hence, we developed an efficient method to classify virus sequences with respect to their species and sub-species (i.e. serotype and/or genotype). This tool provides an easy-to-use software implementation of this new method and was validated on a large dataset assessing the classification performance with respect to whole-genome sequences and partial-genome sequences. Available online: http://krisp.org.za/tools.php.


Assuntos
Vírus Chikungunya/isolamento & purificação , Biologia Computacional/métodos , Vírus da Dengue/isolamento & purificação , Zika virus/isolamento & purificação , Febre de Chikungunya/virologia , Vírus Chikungunya/classificação , Vírus Chikungunya/genética , Dengue/virologia , Vírus da Dengue/classificação , Vírus da Dengue/genética , Genoma Viral , Genótipo , Filogenia , Zika virus/classificação , Zika virus/genética , Infecção por Zika virus/virologia
2.
Bioinformatics ; 2018 Oct 08.
Artigo em Inglês | MEDLINE | ID: mdl-30295730

RESUMO

Summary: Virus sequence data are an essential resource for reconstructing spatiotemporal dynamics of viral spread as well as to inform treatment and prevention strategies. However, the potential benefit for these applications critically depends on accurate and correctly annotated alignments of genetically heterogeneous data. VIRULIGN was built for fast codon-correct alignments of large datasets, with standardized and formalized genome annotation and various alignment export formats. Availability and implementation: VIRULIGN is freely available at https://github.com/rega-cev/virulign as an open source software project. Supplementary information: Supplementary data is available at Bioinformatics online.

3.
Bioinformatics ; 2018 Aug 16.
Artigo em Inglês | MEDLINE | ID: mdl-30124794

RESUMO

Summary: Genome Detective is an easy to use web-based software application that assembles the genomes of viruses quickly and accurately. The application uses a novel alignment method that constructs genomes by reference-based linking of de-novo contigs by combining amino-acids and nucleotide scores. The software was optimized using synthetic datasets to represent the great diversity of virus genomes. The application was then validated with next generation sequencing data of hundreds of viruses. User time is minimal and it is limited to the time required to upload the data. Availability: Available online: http://www.genomedetective.com/app/typingtool/virus/. Supplementary Information: Supplementary data are available at Bioinformatics online.

4.
Virus Evol ; 3(Suppl 1)2017 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-28845257
6.
J Virol ; 88(21): 12882-94, 2014 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-25165112

RESUMO

UNLABELLED: Members of the apolipoprotein B mRNA-editing enzyme-catalytic polypeptide-like-3 (APOBEC3) innate cellular cytidine deaminase family, particularly APOBEC3F and APOBEC3G, can cause extensive and lethal G-to-A mutations in HIV-1 plus-strand DNA (termed hypermutation). It is unclear if APOBEC3-induced mutations in vivo are always lethal or can occur at sublethal levels that increase HIV-1 diversification and viral adaptation to the host. The viral accessory protein Vif counteracts APOBEC3 activity by binding to APOBEC3 and promoting proteasome degradation; however, the efficiency of this interaction varies, since a range of hypermutation frequencies are observed in HIV-1 patient DNA. Therefore, we examined "footprints" of APOBEC3G and APOBEC3F activity in longitudinal HIV-1 RNA pol sequences from approximately 3,000 chronically infected patients by determining whether G-to-A mutations occurred in motifs that were favored or disfavored by these deaminases. G-to-A mutations were more frequent in APOBEC3G-disfavored than in APOBEC3G-favored contexts. In contrast, mutations in APOBEC3F-disfavored contexts were relatively rare, whereas mutations in contexts favoring APOBEC3F (and possibly other deaminases) occurred 16% more often than average G-to-A mutations. These results were supported by analyses of >500 HIV-1 env sequences from acute/early infection. IMPORTANCE: Collectively, our results suggest that APOBEC3G-induced mutagenesis is lethal to HIV-1, whereas mutagenesis caused by APOBEC3F and/or other deaminases may result in sublethal mutations that might facilitate viral diversification. Therefore, Vif-specific cytotoxic T lymphocyte (CTL) responses and drugs that manipulate the interplay between Vif and APOBEC3 may have beneficial or detrimental clinical effects depending on how they affect the binding of Vif to various members of the APOBEC3 family.


Assuntos
Citidina Desaminase/metabolismo , Citosina Desaminase/metabolismo , Infecções por HIV/imunologia , Infecções por HIV/virologia , HIV-1/imunologia , RNA Viral/genética , Produtos do Gene pol do Vírus da Imunodeficiência Humana/genética , Desaminase APOBEC-3G , Humanos , Taxa de Mutação , Mutação Puntual , RNA Viral/metabolismo , Seleção Genética
7.
Bioinformatics ; 29(11): 1477-80, 2013 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-23645815

RESUMO

SUMMARY: RegaDB is a free and open source data management and analysis environment for infectious diseases. RegaDB allows clinicians to store, manage and analyse patient data, including viral genetic sequences. Moreover, RegaDB provides researchers with a mechanism to collect data in a uniform format and offers them a canvas to make newly developed bioinformatics tools available to clinicians and virologists through a user friendly interface. AVAILABILITY AND IMPLEMENTATION: Source code, binaries and documentation are available on http://rega.kuleuven.be/cev/regadb. RegaDB is written in the Java programming language, using a web-service-oriented architecture.


Assuntos
Bases de Dados Factuais , Software , Viroses , Sistemas de Gerenciamento de Base de Dados , Humanos , Viroses/diagnóstico , Viroses/terapia , Viroses/virologia
8.
Infect Genet Evol ; 19: 337-48, 2013 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-23660484

RESUMO

BACKGROUND: To investigate differences in pathogenesis, diagnosis and resistance pathways between HIV-1 subtypes, an accurate subtyping tool for large datasets is needed. We aimed to evaluate the performance of automated subtyping tools to classify the different subtypes and circulating recombinant forms using pol, the most sequenced region in clinical practice. We also present the upgraded version 3 of the Rega HIV subtyping tool (REGAv3). METHODOLOGY: HIV-1 pol sequences (PR+RT) for 4674 patients retrieved from the Portuguese HIV Drug Resistance Database, and 1872 pol sequences trimmed from full-length genomes retrieved from the Los Alamos database were classified with statistical-based tools such as COMET, jpHMM and STAR; similarity-based tools such as NCBI and Stanford; and phylogenetic-based tools such as REGA version 2 (REGAv2), REGAv3, and SCUEAL. The performance of these tools, for pol, and for PR and RT separately, was compared in terms of reproducibility, sensitivity and specificity with respect to the gold standard which was manual phylogenetic analysis of the pol region. RESULTS: The sensitivity and specificity for subtypes B and C was more than 96% for seven tools, but was variable for other subtypes such as A, D, F and G. With regard to the most common circulating recombinant forms (CRFs), the sensitivity and specificity for CRF01_AE was ~99% with statistical-based tools, with phylogenetic-based tools and with Stanford, one of the similarity based tools. CRF02_AG was correctly identified for more than 96% by COMET, REGAv3, Stanford and STAR. All the tools reached a specificity of more than 97% for most of the subtypes and the two main CRFs (CRF01_AE and CRF02_AG). Other CRFs were identified only by COMET, REGAv2, REGAv3, and SCUEAL and with variable sensitivity. When analyzing sequences for PR and RT separately, the performance for PR was generally lower and variable between the tools. Similarity and statistical-based tools were 100% reproducible, but this was lower for phylogenetic-based tools such as REGA (~99%) and SCUEAL (~96%). CONCLUSIONS: REGAv3 had an improved performance for subtype B and CRF02_AG compared to REGAv2 and is now able to also identify all epidemiologically relevant CRFs. In general the best performing tools, in alphabetical order, were COMET, jpHMM, REGAv3, and SCUEAL when analyzing pure subtypes in the pol region, and COMET and REGAv3 when analyzing most of the CRFs. Based on this study, we recommend to confirm subtyping with 2 well performing tools, and be cautious with the interpretation of short sequences.


Assuntos
Infecções por HIV/virologia , HIV-1/classificação , HIV-1/genética , Tipagem Molecular/métodos , Análise por Conglomerados , Biologia Computacional , Bases de Dados Genéticas , Infecções por HIV/epidemiologia , Humanos , Filogenia , Vigilância em Saúde Pública , Reprodutibilidade dos Testes , Sensibilidade e Especificidade
9.
Infect Genet Evol ; 19: 349-60, 2013 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-23523594

RESUMO

We previously modeled the in vivo evolution of human immunodeficiency virus-1 (HIV-1) under drug selective pressure from cross-sectional viral sequences. These fitness landscapes (FLs) were made by using first a Bayesian network (BN) to map epistatic substitutions, followed by scaling the fitness landscape based on an HIV evolution simulator trying to evolve the sequences from treatment naïve patients into sequences from patients failing treatment. In this study, we compared four FLs trained with different sequence populations. Epistatic interactions were learned from three different cross-sectional BNs, trained with sequence from patients experienced with indinavir (BNT), all protease inhibitors (PIs) (BNP) or all PI except indinavir (BND). Scaling the fitness landscape was done using cross-sectional data from drug naïve and indinavir experienced patients (Fcross using BNT) and using longitudinal sequences from patients failing indinavir (FlongT using BNT, FlongP using BNP, FlongD using BND). Evaluation to predict the failing sequence and therapy outcome was performed on independent sequences of patients on indinavir. Parameters included estimated fitness (LogF), the number of generations (GF) or mutations (MF) to reach the fitness threshold (average fitness when a major resistance mutation appeared), the number of generations (GR) or mutations (MR) to reach a major resistance mutation and compared to genotypic susceptibility score (GSS) from Rega and HIVdb algorithms. In pairwise FL comparisons we found significant correlation between fitness values for individual sequences, and this correlation improved after correcting for the subtype. Furthermore, FLs could predict the failing sequence under indinavir-containing combinations. At 12 and 48 weeks, all parameters from all FLs and indinavir GSS (both for Rega and HIVdb) were predictive of therapy outcome, except MR for FlongT and FlongP. The fitness landscapes have similar predictive power for treatment response under indinavir-containing regimen as standard rules-based algorithms, and additionally allow predicting genetic evolution under indinavir selective pressure.


Assuntos
Infecções por HIV/virologia , Inibidores da Protease de HIV/farmacologia , HIV-1/efeitos dos fármacos , HIV-1/genética , Indinavir/farmacologia , Teorema de Bayes , Biologia Computacional , Farmacorresistência Viral/efeitos dos fármacos , Farmacorresistência Viral/genética , Evolução Molecular , Aptidão Genética , Infecções por HIV/tratamento farmacológico , Inibidores da Protease de HIV/uso terapêutico , Humanos , Indinavir/uso terapêutico , Estimativa de Kaplan-Meier , Modelos Estatísticos , Falha de Tratamento , Carga Viral
10.
Retrovirology ; 9: 81, 2012 Oct 03.
Artigo em Inglês | MEDLINE | ID: mdl-23031662

RESUMO

BACKGROUND: The effect of drug resistance transmission on disease progression in the newly infected patient is not well understood. Major drug resistance mutations severely impair viral fitness in a drug free environment, and therefore are expected to revert quickly. Compensatory mutations, often already polymorphic in wild-type viruses, do not tend to revert after transmission. While compensatory mutations increase fitness during treatment, their presence may also modulate viral fitness and virulence in absence of therapy and major resistance mutations. We previously designed a modeling technique that quantifies genotypic footprints of in vivo treatment selective pressure, including both drug resistance mutations and polymorphic compensatory mutations, through the quantitative description of a fitness landscape from virus genetic sequences. RESULTS: Genotypic correlates of viral load and CD4 cell count were evaluated in subtype B sequences from recently diagnosed treatment-naive patients enrolled in the SPREAD programme. The association of surveillance drug resistance mutations, reported compensatory mutations and fitness estimated from drug selective pressure fitness landscapes with baseline viral load and CD4 cell count was evaluated using regression techniques. Protease genotypic variability estimated to increase fitness during treatment was associated with higher viral load and lower CD4 cell counts also in treatment-naive patients, which could primarily be attributed to well-known compensatory mutations at highly polymorphic positions. By contrast, treatment-related mutations in reverse transcriptase could not explain viral load or CD4 cell count variability. CONCLUSIONS: These results suggest that polymorphic compensatory mutations in protease, reported to be selected during treatment, may improve the replicative capacity of HIV-1 even in absence of drug selective pressure or major resistance mutations. The presence of this polymorphic variation may either reflect a history of drug selective pressure, i.e. transmission from a treated patient, or merely be a result of diversity in wild-type virus. Our findings suggest that transmitted drug resistance has the potential to contribute to faster disease progression in the newly infected host and to shape the HIV-1 epidemic at a population level.


Assuntos
Fármacos Anti-HIV/uso terapêutico , Contagem de Linfócito CD4 , Infecções por HIV/tratamento farmacológico , HIV-1/enzimologia , Peptídeo Hidrolases/genética , Polimorfismo Genético , Carga Viral , Proteínas Virais/genética , Adulto , Farmacorresistência Viral , Feminino , Infecções por HIV/imunologia , Infecções por HIV/virologia , HIV-1/efeitos dos fármacos , HIV-1/genética , HIV-1/fisiologia , Humanos , Masculino , Peptídeo Hidrolases/metabolismo , Estudos Prospectivos , Proteínas Virais/metabolismo
11.
PLoS One ; 7(9): e42123, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-22970114

RESUMO

BACKGROUND: It is estimated that 15 to 20 million people are infected with the human T-cell lymphotropic virus type 1 (HTLV-1). At present, there are more than 2,000 unique HTLV-1 isolate sequences published. A central database to aggregate sequence information from a range of epidemiological aspects including HTLV-1 infections, pathogenesis, origins, and evolutionary dynamics would be useful to scientists and physicians worldwide. Described here, we have developed a database that collects and annotates sequence data and can be accessed through a user-friendly search interface. The HTLV-1 Molecular Epidemiology Database website is available at http://htlv1db.bahia.fiocruz.br/. METHODOLOGY/PRINCIPAL FINDINGS: All data was obtained from publications available at GenBank or through contact with the authors. The database was developed using Apache Webserver 2.1.6 and SGBD MySQL. The webpage interfaces were developed in HTML and sever-side scripting written in PHP. The HTLV-1 Molecular Epidemiology Database is hosted on the Gonçalo Moniz/FIOCRUZ Research Center server. There are currently 2,457 registered sequences with 2,024 (82.37%) of those sequences representing unique isolates. Of these sequences, 803 (39.67%) contain information about clinical status (TSP/HAM, 17.19%; ATL, 7.41%; asymptomatic, 12.89%; other diseases, 2.17%; and no information, 60.32%). Further, 7.26% of sequences contain information on patient gender while 5.23% of sequences provide the age of the patient. CONCLUSIONS/SIGNIFICANCE: The HTLV-1 Molecular Epidemiology Database retrieves and stores annotated HTLV-1 proviral sequences from clinical, epidemiological, and geographical studies. The collected sequences and related information are now accessible on a publically available and user-friendly website. This open-access database will support clinical research and vaccine development related to viral genotype.


Assuntos
Acesso à Informação , Mineração de Dados , Bases de Dados de Ácidos Nucleicos , Vírus Linfotrópico T Tipo 1 Humano/genética , Epidemiologia Molecular , Sequência de Bases , Geografia , Infecções por HTLV-I/epidemiologia , Infecções por HTLV-I/genética , Infecções por HTLV-I/virologia , Humanos , Interface Usuário-Computador
12.
PLoS Genet ; 8(3): e1002550, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-22457633

RESUMO

The rapid evolution of Human Immunodeficiency Virus (HIV-1) allows studies of ongoing host-pathogen interactions. One key selective host factor is APOBEC3G (hA3G) that can cause extensive and inactivating Guanosine-to-Adenosine (G-to-A) mutation on HIV plus-strand DNA (termed hypermutation). HIV can inhibit this innate anti-viral defense through binding of the viral protein Vif to hA3G, but binding efficiency varies and hypermutation frequencies fluctuate in patients. A pivotal question is whether hA3G-induced G-to-A mutation is always lethal to the virus or if it may occur at sub-lethal frequencies that could increase viral diversification. We show in vitro that limiting-levels of hA3G-activity (i.e. when only a single hA3G-unit is likely to act on HIV) produce hypermutation frequencies similar to those in patients and demonstrate in silico that potentially non-lethal G-to-A mutation rates are ∼10-fold lower than the lowest observed hypermutation levels in vitro and in vivo. Our results suggest that even a single incorporated hA3G-unit is likely to cause extensive and inactivating levels of HIV hypermutation and that hypermutation therefore is typically a discrete "all or nothing" phenomenon. Thus, therapeutic measures that inhibit the interaction between Vif and hA3G will likely not increase virus diversification but expand the fraction of hypermutated proviruses within the infected host.


Assuntos
Citidina Desaminase/genética , HIV-1/genética , Interações Hospedeiro-Patógeno , Produtos do Gene vif do Vírus da Imunodeficiência Humana/metabolismo , Desaminase APOBEC-3G , Citidina Desaminase/metabolismo , Infecções por HIV/genética , Infecções por HIV/metabolismo , HIV-1/metabolismo , Humanos , Mutação , Provírus/genética , Provírus/crescimento & desenvolvimento , Replicação Viral , Produtos do Gene vif do Vírus da Imunodeficiência Humana/genética
13.
BMC Bioinformatics ; 11: 409, 2010 Aug 03.
Artigo em Inglês | MEDLINE | ID: mdl-20682040

RESUMO

BACKGROUND: Failure on Highly Active Anti-Retroviral Treatment is often accompanied with development of antiviral resistance to one or more drugs included in the treatment. In general, the virus is more likely to develop resistance to drugs with a lower genetic barrier. Previously, we developed a method to reverse engineer, from clinical sequence data, a fitness landscape experienced by HIV-1 under nelfinavir (NFV) treatment. By simulation of evolution over this landscape, the individualized genetic barrier to NFV resistance may be estimated for an isolate. RESULTS: We investigated the association of estimated genetic barrier with risk of development of NFV resistance at virological failure, in 201 patients that were predicted fully susceptible to NFV at baseline, and found that a higher estimated genetic barrier was indeed associated with lower odds for development of resistance at failure (OR 0.62 (0.45 - 0.94), per additional mutation needed, p = .02). CONCLUSIONS: Thus, variation in individualized genetic barrier to NFV resistance may impact effective treatment options available after treatment failure. If similar results apply for other drugs, then estimated genetic barrier may be a new clinical tool for choice of treatment regimen, which allows consideration of available treatment options after virological failure.


Assuntos
Farmacorresistência Viral , Infecções por HIV/tratamento farmacológico , HIV-1/efeitos dos fármacos , HIV-1/genética , Fármacos Anti-HIV/farmacologia , Fármacos Anti-HIV/uso terapêutico , Infecções por HIV/virologia , Protease de HIV/genética , Humanos , Mutação , Nelfinavir/farmacologia , Nelfinavir/uso terapêutico , Falha de Tratamento
14.
Nucleic Acids Res ; 37(Web Server issue): W634-42, 2009 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-19483099

RESUMO

Human immunodeficiency virus type-1 (HIV-1), hepatitis B and C and other rapidly evolving viruses are characterized by extremely high levels of genetic diversity. To facilitate diagnosis and the development of prevention and treatment strategies that efficiently target the diversity of these viruses, and other pathogens such as human T-lymphotropic virus type-1 (HTLV-1), human herpes virus type-8 (HHV8) and human papillomavirus (HPV), we developed a rapid high-throughput-genotyping system. The method involves the alignment of a query sequence with a carefully selected set of pre-defined reference strains, followed by phylogenetic analysis of multiple overlapping segments of the alignment using a sliding window. Each segment of the query sequence is assigned the genotype and sub-genotype of the reference strain with the highest bootstrap (>70%) and bootscanning (>90%) scores. Results from all windows are combined and displayed graphically using color-coded genotypes. The new Virus-Genotyping Tools provide accurate classification of recombinant and non-recombinant viruses and are currently being assessed for their diagnostic utility. They have incorporated into several HIV drug resistance algorithms including the Stanford (http://hivdb.stanford.edu) and two European databases (http://www.umcutrecht.nl/subsite/spread-programme/ and http://www.hivrdb.org.uk/) and have been successfully used to genotype a large number of sequences in these and other databases. The tools are a PHP/JAVA web application and are freely accessible on a number of servers including: http://bioafrica.mrc.ac.za/rega-genotype/html/, http://lasp.cpqgm.fiocruz.br/virus-genotype/html/, http://jose.med.kuleuven.be/genotypetool/html/.


Assuntos
Variação Genética , Software , Vírus/classificação , Sequência de Bases , Genótipo , HIV-1/classificação , HIV-1/genética , Hepacivirus/classificação , Hepacivirus/genética , Vírus da Hepatite B/classificação , Vírus da Hepatite B/genética , Filogenia , Recombinação Genética , Padrões de Referência , Alinhamento de Sequência , Análise de Sequência/normas , Vírus/genética
15.
Infect Genet Evol ; 9(4): 683-8, 2009 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-19038365

RESUMO

OBJECTIVE: The overall prevalence of the K65R mutation in HIV-1 reverse transcriptase has increased in treatment-experienced patients, mostly attributed to the increasing use of tenofovir (TDF). A number of TDF-based regimens are associated with high rate of early virological failure. In this study, we evaluated the impact of these combinations on K65R selection over time. METHODS: Treatment-experienced patients who had a genotypic resistance test at time of failure in the period 2002-2005 in a hospital in Lisbon were included. Incidence of K65R was calculated and compared with proportions of failing therapies in the respective year of sampling including TDF or didanosine plus stavudine and their respective frequency of K65R selection were analyzed using classical statistics and Bayesian Network Learning. RESULTS: The overall rate of K65R in the database was consistent with earlier reports. The incidence of K65R increased in the period 2002-2004 but showed a sharp, significant decrease in 2005, despite a continuous increase of patients failing TDF-based regimens. The proportion of patients failing certain not-recommended regimens decreased sharply in 2005 and therefore correlated well with K65R incidence trend. CONCLUSIONS: This study suggests that the use of certain TDF-based regimens caused the increase in K65R incidence over the last years.


Assuntos
Adenina/análogos & derivados , Fármacos Anti-HIV/uso terapêutico , Farmacorresistência Viral , Infecções por HIV/tratamento farmacológico , Transcriptase Reversa do HIV/genética , HIV-1/genética , Organofosfonatos/uso terapêutico , Inibidores da Transcriptase Reversa/efeitos adversos , Adenina/farmacologia , Adenina/uso terapêutico , Fármacos Anti-HIV/farmacologia , Teorema de Bayes , Interpretação Estatística de Dados , Bases de Dados de Ácidos Nucleicos , Infecções por HIV/epidemiologia , Infecções por HIV/virologia , Humanos , Mutação , Organofosfonatos/farmacologia , Portugal/epidemiologia , Estudos Retrospectivos , Inibidores da Transcriptase Reversa/uso terapêutico , Tenofovir
16.
AIDS ; 22(16): 2107-15, 2008 Oct 18.
Artigo em Inglês | MEDLINE | ID: mdl-18832874

RESUMO

OBJECTIVE: To clarify the role of novel mutations selected by treatment with efavirenz or nevirapine, and investigate the influence of HIV-1 subtype on nonnucleoside reverse transcriptase inhibitor (nNRTI) resistance pathways. DESIGN: By finding direct dependencies between treatment-selected mutations, the involvement of these mutations as minor or major resistance mutations against efavirenz, nevirapine, or coadministrated nucleoside analogue reverse transcriptase inhibitors (NRTIs) is hypothesized. In addition, direct dependencies were investigated between treatment-selected mutations and polymorphisms, some of which are linked with subtype, and between NRTI and nNRTI resistance pathways. METHODS: Sequences from a large collaborative database of various subtypes were jointly analyzed to detect mutations selected by treatment. Using Bayesian network learning, direct dependencies were investigated between treatment-selected mutations, NRTI and nNRTI treatment history, and known NRTI resistance mutations. RESULTS: Several novel minor resistance mutations were found: 28K and 196R (for resistance against efavirenz), 101H and 138Q (nevirapine), and 31L (lamivudine). Robust interactions between NRTI mutations (65R, 74V, 75I/M, and 184V) and nNRTI resistance mutations (100I, 181C, 190E and 230L) may affect resistance development to particular treatment combinations. For example, an interaction between 65R and 181C predicts that the nevirapine and tenofovir and lamivudine/emtricitabine combination should be more prone to failure than efavirenz and tenofovir and lamivudine/emtricitabine. CONCLUSION: Bayesian networks were helpful in untangling the selection of mutations by NRTI versus nNRTI treatment, and in discovering interactions between resistance mutations within and between these two classes of inhibitors.


Assuntos
Fármacos Anti-HIV/farmacologia , Benzoxazinas/farmacologia , Farmacorresistência Viral/genética , HIV-1/efeitos dos fármacos , Nevirapina/farmacologia , Teorema de Bayes , Bases de Dados Factuais , Transcriptase Reversa do HIV/antagonistas & inibidores , HIV-1/genética , Humanos , Mutação , Inibidores da Transcriptase Reversa/farmacologia , Transdução de Sinais
17.
Antivir Ther ; 13(3): 399-407, 2008.
Artigo em Inglês | MEDLINE | ID: mdl-18572753

RESUMO

BACKGROUND: A method has been developed to estimate a fitness landscape experienced by HIV-1 under treatment selective pressure as a function of the genotypic sequence thereby also estimating the genetic barrier to resistance. METHODS: We evaluated the performance of two estimated fitness landscapes (nelfinavir [NFV] and zidovudine [AZT] plus lamivudine [3TC]) to predict week 12 viral load (VL) change for 176 treatment change episodes (TCEs) and probability of week 48 virological failure for 90 TCEs, in treatment experienced patients starting these drugs in combination. RESULTS: A higher genetic barrier for AZT plus 3TC, (quantified per additional mutation required to develop resistance against these drugs) was associated with a 0.54 (95% confidence interval [CI] 0.30-0.77) larger log10 VL reduction at 12 weeks (P < 0.0001) and a 0.39 (95%/ CI 0.23-0.66) lower odds of virological failure at 48 weeks (P = 0.0005), in analyses adjusting for the pre-TCE VL and the exact time-lag between the TCE and the date of determining response VL. The strength of these associations was comparable with those seen with expert interpretation systems (Rega, ANRS and HIVDB). A higher genetic barrier to NFV resistance was the only genotypic predictor that tended to be associated with a 0.19 (95% CI 0-0.39) higher log10 VL reduction at 12 weeks (P = 0.05) and a 0.63 (95% CI 0.36-1.09) lower odds of virological failure at 48 weeks ( P = 0.10) per additional mutation. CONCLUSIONS: These results suggest that an estimated genetic barrier derived from fitness landscapes may contribute to an improvement of predicted treatment outcome for NFV and this approach should be explored for other drugs.


Assuntos
Farmacorresistência Viral/genética , Infecções por HIV/tratamento farmacológico , Inibidores da Protease de HIV/uso terapêutico , HIV-1/efeitos dos fármacos , Modelos Biológicos , Inibidores da Transcriptase Reversa/uso terapêutico , Zidovudina/uso terapêutico , Adulto , Quimioterapia Combinada , Feminino , Genótipo , Infecções por HIV/virologia , HIV-1/genética , Humanos , Lamivudina/uso terapêutico , Masculino , Pessoa de Meia-Idade , Mutação , Nelfinavir/uso terapêutico , Valor Preditivo dos Testes , Estudos Retrospectivos , Fatores de Tempo , Falha de Tratamento , Carga Viral
18.
AIDS Res Hum Retroviruses ; 24(3): 355-62, 2008 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-18327983

RESUMO

This study is the first prospective study to assess the prevalence, epidemiology, and risk factors of HIV-1 drug resistance in newly diagnosed HIV-infected patients in Belgium. In January 2003 it was initiated as part of the pan-European SPREAD program, and continued thereafter for four inclusion rounds until December 2006. Epidemiological, clinical, and behavioral data were collected using a standardized questionnaire and genotypic resistance testing was done on a sample taken within 6 months of diagnosis. Two hundred and eighty-five patients were included. The overall prevalence of transmitted HIV-1 drug resistance in Belgium was 9.5% (27/285, 95% CI: 6.6-13.4). Being infected in Belgium, which largely coincided with harboring a subtype B virus, was found to be significantly associated with transmission of drug resistance. The relatively high rate of baseline resistance might jeopardize the success of first line treatment as more than 1 out of 10 (30/285, 10.5%) viruses did not score as fully susceptible to one of the recommended first-line regimens, i.e., zidovudine, lamivudine, and efavirenz. Our results support the implementation of genotypic resistance testing as a standard of care in all treatment-naive patients in Belgium.


Assuntos
Farmacorresistência Viral/genética , Infecções por HIV/epidemiologia , Infecções por HIV/virologia , HIV-1/efeitos dos fármacos , HIV-1/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Fármacos Anti-HIV/farmacologia , Bélgica/epidemiologia , Feminino , Genótipo , Infecções por HIV/fisiopatologia , Infecções por HIV/transmissão , Protease de HIV/genética , Transcriptase Reversa do HIV/genética , HIV-1/isolamento & purificação , Humanos , Masculino , Pessoa de Meia-Idade , Dados de Sequência Molecular , Estudos Prospectivos , RNA Viral/sangue , RNA Viral/genética , RNA Viral/isolamento & purificação , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Análise de Sequência de DNA , Inquéritos e Questionários
19.
J Antimicrob Chemother ; 61(6): 1201-4, 2008 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-18356151

RESUMO

OBJECTIVES: Non-B human immunodeficiency virus (HIV)-1 subtypes possess several amino acid signatures in the viral protease that distinguish them from subtype B, some of which are reported as secondary drug-related mutations. We have previously shown a strong statistical interdependency of residues 71, 89 and 90 in subtype G, but the impact of substitutions on protease inhibitor (PI) resistance is unknown. PATIENTS AND METHODS: We selected subtype G viruses from patients with diverse amino acid combinations at codons 71 (A/T), 74 (T/S), 89 (I/L/M/V) and 90 (L/M). Viral protease genes were inserted into an HIV molecular clone (HXB2). PI drug susceptibilities of chimeric viruses were determined. RESULTS: In isolates displaying 89I/V in combination with A71 or T74, a reversal to subtype G wild-type 89M was observed after growth in the absence of PI. The presence of 71T in one isolate and 74S in another allowed the persistence of 89I. Mutation 90M conferred intermediate but significant degrees of drug resistance to ritonavir and nelfinavir in subtype G viruses. The combination of 71T or 74S, 89I and 90M resulted in higher levels of resistance to those PIs. CONCLUSIONS: Our results point to the hypothesis that 71T or 74S stabilizes 89I in the protease of subtype G, whose association was previously seen by Bayesian network analyses. The association of 89I with 90M may further increase the PI resistance of subtype G viruses when compared with 90M alone, highlighting novel mutational profiles for drug resistance in this non-B subtype.


Assuntos
Substituição de Aminoácidos/genética , Farmacorresistência Viral/genética , Inibidores da Protease de HIV/farmacologia , Protease de HIV/genética , HIV-1/efeitos dos fármacos , HIV-1/genética , Genótipo , Infecções por HIV/virologia , HIV-1/classificação , HIV-1/isolamento & purificação , Humanos , Testes de Sensibilidade Microbiana , Mutação , Análise de Sequência de DNA
20.
Retrovirology ; 5: 12, 2008 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-18241328

RESUMO

Despite improvements in HIV treatment, the prevalence of multidrug resistance and full class resistance is still reported to be increasing. However, to investigate whether current treatment strategies are still selecting for multidrug and full class resistance, the incidence, instead of the prevalence, is more informative. Temporal trends in multidrug resistance (MDR defined as at most 1 drug fully susceptible) and full class resistance (FCR defined as no drug in this class fully susceptible) in Portugal based on 3394 viral isolates genotyped from 2000 to 2006 were examined using the Rega 6.4.1 interpretation system. From July 2001 to July 2006 there was a significant decreasing trend of MDR with 5.7%, 5.2%, 3.8%, 3.4% and 2.7% for the consecutive years (P = 0.003). Multivariate analysis showed that for every consecutive year the odds of having a new MDR case decreased with 20% (P = 0.003). Furthermore, a decline was observed for NRTI- and PI-FCR (both P < 0.001), whereas for NNRTI-FCR a parabolic trend over time was seen (P < 0.001), with a maximum incidence in 2003-'04. Similar trends were obtained when scoring resistance for only one drug within a class or by using another interpretation system. In conclusion, the incidence of multidrug and full class resistance is decreasing over time in Portugal, with the exception of NNRTI full class resistance which showed an initial rise, but subsequently also a decline. This is most probably reflecting the changing drug prescription, the increasing efficiency of HAART and the improved management of HIV drug resistance. This work was presented in part at the Eighth International Congress on Drug Therapy in HIV Infection, Glasgow (UK), 12-16 November 2006 (PL5.5); and at the Fifth European HIV Drug Resistance Workshop, Cascais (Portugal), 28-30 March 2007 (Abstract 1).


Assuntos
Fármacos Anti-HIV/farmacologia , Infecções por HIV/prevenção & controle , Infecções por HIV/virologia , HIV-1/efeitos dos fármacos , Fármacos Anti-HIV/uso terapêutico , Terapia Antirretroviral de Alta Atividade , Farmacorresistência Viral Múltipla , Infecções por HIV/tratamento farmacológico , Infecções por HIV/epidemiologia , HIV-1/classificação , Humanos , Incidência , Estudos Longitudinais , Portugal/epidemiologia
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