Drugs belonging to three different classesnucleoside analogue reverse transcriptase. Seq program of the stanford database for interpretation and simultaneously to virconet analysis on a. The scientific goal is to determine which mutations of the human immunodeficiency virus type 1 hiv1 are associated with drug resistance. To evaluate possible sample contamination maximum likelihood phylogenetic tree of hiv1 pol gene protease and reverse transcriptase from samples processed by. First, the mutational tolerance of hiv 1 protease is well characterized. Human immunodeficiency virus reverse transcriptase and protease. Second, hiv 1 protease is under at least three structural and. However, viral drug resistance to pis could emerge rapidly thus reducing the effectiveness of those drugs. Sequences in fasta format or plain text can be pasted in the text box option a or uploaded option b. The program then returns a separate table for each observed mutation at that. Current drug resistance genotyping methods are costly, optimized for subtype b virus, and primarily detect resistance mutations to protease and reverse transcriptase inhibitors.
Literature prevalence of mutations in submitted sequences. Comparative evaluation of three computerized algorithms. Mutations conferring resistance to antiretroviral drugs are based on comparing gene sequences with corresponding consensus. Prevalence of transmitted drugresistance mutations and. Pdf knowledge integration of software for hiv drug. It has been recompiled in 2008 listing 93 common mutations, after its initial mutation compilation in 2007 of 80 mutations. Of note, all current fdaapproved pis are competitive inhibitors, i. Extending hivdb functionality while securing data privacy abstract the tremendous impact that hiv has had on the world can not only be seen in the striking current hiv statistics, but also in the. Previous treatment failure with a pi containing regimen may elicit resistance mutations, reducing pi susceptibility and limiting treatment options. The software needed to implement these algorithms should remain stable to allow direct comparison between emerging algorithms and their component rules. The merops database is an information resource for peptidases also termed proteases, proteinases and proteolytic enzymes and the proteins that inhibit them. Jan 09, 2017 the merops database is an information resource for peptidases also termed proteases, proteinases and proteolytic enzymes and the proteins that inhibit them. Access to antiretroviral drugs for hiv1 infection has increased in subsaharan africa ssa during the past few years.
Structures of protease hiv drug resistance database stanford. Sep 12, 2012 human immunodeficiency virus type 1 hiv 1 protease inhibitors pis are the most potent class of drugs in antiretroviral therapies. Accessory mutations balance the marginal stability of the. Hiv human immunodeficiency virus is a virus that attacks the immune system, the bodys natural defense system. Risk factors and outcomes for the q151m and t69 insertion. The aim of the present study was to evaluate the resistanceassociated mutations in 302 human immunodeficiency virus type 1 hiv 1infected patients receiving combination therapy and monitored in marseille, france, hospitals from january 1997 to june 1998.
Mutations in the hiv 1 genome are often associated with treatment failure as indicated by viral replication and elevated levels of virus in the blood. The higher barrier of darunavir and tipranavir resistance for. Hiv 1 protease cannot cleave them, so they stay lodged in the active site, blocking the normal function of the enzyme. Sep 09, 2011 in total, nine hiv 1 protease inhibitors have been approved by the u. In the 99 amino acid residue hiv 1 protease, 36 mutation loci have been identified which lead to various levels of resistance to protease inhibitor treatment 1,2. For subtyping purposes, all the nucleotide sequences were submitted to the stanford database. Prediction of hiv1 protease inhibitor resistance by. Bradley betts, phd, a software developer in radiology, was a graduate student in the engineering department when he helped develop the program for the stanford hiv rt and protease sequence database. The levels of viral resistance to protease and reverse transcriptase inhibitors were predicted by the hivdb.
Human immunodeficiency virus reverse transcriptase and. Low accumulation of l90m in protease from subtype f hiv1. Hiv1 genotypic resistance test grt interpretation systems is require updates as new studies on hiv1 drug resistance are published and as treatment guidelines evolve. Prevalence of reverse transcriptase and protease mutations. Known as the stanford hiv rt and protease sequence. Both the virus and the infection it causes are called hiv. Mutation frequencies at each position of protease or rt according to subtype and. Hivdb criteria for classifying rt, protease and integrase mutations.
The hiv reverse transcriptase and protease sequence database is an online relational database that catalogues evolutionary and drugrelated sequence variation in the human immunodeficiency virus. Analysis of hiv drug resistance data stanford university. The summary page describing a given peptidase can be reached by use of an index under its name, merops identifier or source organism. The hivdb system for hiv1 genotypic resistance interpretation. The data set, publicly available from the stanford hiv drug resistance database, was originally analyzed in rhee et al. Hiv drug resistance interpretation algorithms will continue to evolve with the publication of new data and the introduction of new antiretroviral inhibitors. Comparative evaluation of three computerized algorithms for. Viral resistance to antiretroviral therapy threatens our best methods to control and prevent hiv infection. For subtyping purposes, allthe nucleotide sequences were submitted to the. The hiv reverse transcriptase and protease sequence database is an online relational. Publicly available databases have revolutionized how biological research is.
Without a strong immune system, the body has trouble fighting off disease. Dec 23, 2014 viral resistance to antiretroviral therapy threatens our best methods to control and prevent hiv infection. All sequences were analyzed for the presence of hypermutations using hypermut software v2. The stanford protease and rt database allows users to screen their own sequences for resistanceconferring mutations and compare them to stored sequences. Download fullsize image genmol software is used for predicting hiv1 protease inhibitor pi resistance. Background protease inhibitors pi are especially important in salvage therapy. Oct 24, 2012 accurate interpretation of hiv drug resistance hivdr testing is challenging, yet important for patient care. We selected the data for which genotypic and phenotypic.
A curated database containing nearly all published hiv rt and protease sequences. We compared genotyping interpretation, based on the stanford university hiv drug resistance database stanford hivdb, and virtual phenotyping, based on the janssen diagnostics bvbas vircotype hiv1, and investigated their level of agreement in antiretroviral arv naive. Accessory mutations balance the marginal stability of the hiv. Crossclade simultaneous hiv drug resistance genotyping for. Accurate interpretation of hiv drug resistance hivdr testing is challenging, yet important for patient care.
A total of 1792 hiv 1 protease sequences and their corresponding ic 50 values were retrieved from the stanford hiv drug resistance database. Nucleotide sequences can be entered in fasta format or plain text. Arv selection data comprising 168,662 protease, 178,122 rt and 21,549 integrase hiv1 virus sequences from 187,693 persons. Hiv1 protease cannot cleave them, so they stay lodged in the active site, blocking the normal function of the enzyme.
The sequences of the protease and reverse transcriptase genes were aligned. Crossclade simultaneous hiv drug resistance genotyping. One hundred and six hiv sequences derived from hiv. Mutation patterns of the reverse transcriptase and protease. The first program, hivseq, accepts usersubmitted rt and protease.
Sanger and next generation sequencing approaches to. Access to antiretroviral drugs for hiv 1 infection has increased in subsaharan africa ssa during the past few years. Seq program of the stanford database for interpretation and simultaneously to virconet analysis on a commercial basis. The scientific goal is to determine which mutations of the human immunodeficiency virus type 1 hiv 1 are associated with drug resistance. Risk factors and outcomes for the q151m and t69 insertion hiv. The lanl hiv resistance mutation database is no longer maintained. Database queries and references info relating to genotypetreatment correlations, genotype clinical outcome correlations, references, new submissions to database 2. In figure 3 a, the maximum fold resistance of the double mutants among the 1808 isolates is plotted against the calculated stability change g for the. Polymorphisms and resistance mutations in the protease and. Jun 01, 2005 backgroundthis work evaluates the role of subtype f human immunodeficiency virus type 1 hiv 1 protease pr substitutions l89m and l90m in viral replication and resistance to pr inhibitors pis methods subtype b and f pr genes were subjected to sitedirected mutagenesis, to create and reverse the methionine at positions 89 and 90. Hivseq program hiv drug resistance database stanford university. Extending hivdb functionality while securing data privacy abstract the tremendous impact that hiv has had on the world can not only be seen in the striking current hiv statistics, but also in the enormous amount of information related to hiv that is generated on almost a daily basis. The stanford hiv drug resistance database hosts a freely available online. A total of 1792 hiv1 protease sequences and their corresponding ic 50 values were retrieved from the stanford hiv drug resistance database.
Formatted sequences were submitted to stanford hiv rt and protease sequence database to determine the hivdr mutation profile as defined in who surveillance mutation list 2009 proposed by bennett et. Apr 16, 2018 the identification of drug resistance mutations was based on output from the stanford university hiv drug resistance database program. The hivdb program on the web accepts usersubmitted protease and rt. Previous treatment failure with a pi containing regimen may elicit resistance mutations, reducing pi susceptibility and.
Prediction of mutational tolerance in hiv1 protease and. Human immunodeficiency virus hiv replication is markedly inhibited by highly active antiretroviral drug combinations. Drug susceptibility data comprising 25,434 pi, 19,858 nrti, 11,548 nnrti and 4,606 ini susceptibility results from hiv 1 virus isolates. Mutation frequencies at each position of protease or rt according to subtype. The higher barrier of darunavir and tipranavir resistance.
Mutation patterns of the reverse transcriptase and. Hiv drug resistance testing using the stanford university. Stanford hivdb program hivdb, the visible geneticsbayer diagnostics guidelines 6. Resistance genotyping was performed by using big dye terminator chemistry provided by the viroseq genotyping system. The three hiv targets currently in hivdb are protease pr, reverse. Hivdb accepts usersubmitted protease, rt, and integrase sequences or mutations and returns inferred levels of resistance to the most commonly used protease, nucleoside, nonnucleoside, and integrase inhibitors. Formatted sequences were submitted to stanford hiv rt and protease sequence database to determine the hivdr mutation profile as defined in who surveillance mutation list 2009 proposed by bennett et al. It is critically important to understand the basis of this resistance for designing new drugs. We selected the data for which genotypic and phenotypic evaluations were performed by virologic, inc.
Drug resistance has sharply limited the effectiveness of hiv1 protease inhibitors in aids therapy. The current hiv 1 protease inhibitors are designed with a hydroxyl group. Hiv1 protease pr is a retroviral aspartyl protease retropepsin, an enzyme involved with peptide bond hydrolysis in retroviruses, that is essential for the lifecycle of hiv, the retrovirus that causes aids. Known as the stanford hiv rt and protease sequence database, it includes information on the two key proteins targeted by hiv drugs. Current drug resistance genotyping methods are costly, optimized for subtype b virus. Rationale and uses of a public hiv drugresistance database. The aim of this study was to describe major pi mutations among patients exposed to at least one pi to evaluate predictors of mutation emergence and the impact of. Bradley betts, phd, a software developer in radiology, was a graduate student in the engineering department when he helped develop the program for the stanford hiv rt and protease sequence. Hiv gene sequence analysis for drug resistance studies. New stanford list of hiv mutations vital to tracking aids.
Drugs belonging to three different classesnucleoside analogue reverse transcriptase rt inhibitors nrtis, nonnrtis nnrtis, and protease inhibitors pisare currently used in various combinations to treat hivinfected patients 3, 14, 20, 43. In the reverse transcriptase rt gene, the most frequent mutations were found at codons 215 53%, 41 34%, and 67, 70, 184, and 210. Mutations in the hiv1 genome are often associated with treatment failure as. Mar 06, 2009 the data used in the study was derived from a publicly available, searchable database that shafer and his colleagues began at stanford in 1998. Sequences were obtained from clinical practice and from published sequences in the stanford hiv 1 rt and protease sequence database. You can create similar pictures of these drug complexes by clicking on the pdb accession codes above, and then picking one of the options for 3d viewing. Hiv 1 protease pr is a retroviral aspartyl protease retropepsin, an enzyme involved with peptide bond hydrolysis in retroviruses, that is essential for the lifecycle of hiv, the retrovirus that causes aids. White blood cells are an important part of the immune system. More recently, the researchers have begun gathering resistance data on integrase inhibitors, the latest class of antiretroviral drugs to be introduced. Virologic failure on antiretroviral therapy without hiv drug. Virologic failure on antiretroviral therapy without hiv.
The long term success of hivdb and other biomedical databases. Terms of use faqs hiv drug resistance database stanford. New list of hiv mutations vital to tracking aids epidemic. Instead, we recommend the following current resources. The data set, publicly available from the stanford hiv drug. Hivalg program hiv drug resistance database stanford university. Hivdb program hiv drug resistance database stanford university. First, the mutational tolerance of hiv1 protease is well characterized. Extending hivdb functionality while securing data privacy. Hiv drug resistance database, also known as stanford hiv rt and protease sequence database is a database at stanford university that tracks 93 common mutations of hiv. Hiv protease cleaves newly synthesized polyproteins namely, gag and gag pol at nine cleavage sites to create the mature protein.
With the increasing use of integrase inhibitors in firstline therapies, monitoring for integrase inhibitor. Arv selection data comprising 168,662 protease, 178,122 rt and 21,549 integrase hiv 1 virus sequences from 187,693 persons. The identification of drug resistance mutations was based on output from the stanford university hiv drug resistance database program. Interdisciplinary initiatives program round 1 2000. Following established convention and software output , the term t69i mutation is used throughout to refer to any insertion in the. Hivseq accepts usersubmitted rt, protease, and integrase sequences or. The aim of the present study was to evaluate the resistanceassociated mutations in 302 human immunodeficiency virus type 1 hiv1infected patients receiving combination therapy and monitored. Stanford university hiv drug resistance database website an online database created from published hiv sequences. From the analysis of the hiv life cycle, one could con. The data used in the study was derived from a publicly available, searchable database that shafer and his colleagues began at stanford in 1998.
The stanford hiv drug resistance database hivdb is an essential resource for public health officials monitoring adr and tdr, for scientists developing new arv drugs, and for hiv care providers managing patients with hivdr. All the studied strains were found to harbor accessory mutations in the protease gene. Stanford hiv resistance database provides web services and related pages as a. For subtyping purposes, allthe nucleotide sequences were submitted to the stanford database. The sequences of the protease and reverse transcriptase genes were aligned clustalw and a phylogenetic tree was built mega 3 software. Backgroundthis work evaluates the role of subtype f human immunodeficiency virus type 1 hiv1 protease pr substitutions l89m and l90m in viral replication and resistance to.
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