In this study, the in vitro inhibitory efficacy was tested against a mdr. Sanger and next generation sequencing approaches to. Known as the stanford hiv rt and protease sequence database, it includes information on the two key proteins targeted by hiv drugs. Analysis of hiv drug resistance data stanford university. We selected the data for which genotypic and phenotypic evaluations were performed by virologic, inc. Sequences were obtained from clinical practice and from published sequences in the stanford hiv1 rt and protease sequence database. Genetic diversity of protease and reverse transcriptase.
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. Sequences were obtained from clinical practice and from published sequences in the stanford hiv 1 rt and protease sequence database. 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. Low accumulation of l90m in protease from subtype f hiv1. Literature prevalence of mutations in submitted sequences. Stanford hiv resistance database provides web services and related pages as a. 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. Hiv1 genotypic resistance test grt interpretation systems is require updates as new studies on hiv1 drug resistance are published and as treatment guidelines evolve. The stanford hiv drug resistance database hosts a freely available online. Following established convention and software output , the term t69i mutation is used throughout to refer to any insertion in the.
Hivdb program hiv drug resistance database stanford university. The sequences of the protease and reverse transcriptase genes were aligned. The three hiv targets currently in hivdb are protease pr, reverse. The higher barrier of darunavir and tipranavir resistance for.
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. A total of 1792 hiv 1 protease sequences and their corresponding ic 50 values were retrieved from the stanford hiv drug resistance database. The first program, hivseq, accepts usersubmitted rt and protease. All sequences were analyzed for the presence of hypermutations using hypermut software v2. Drugs belonging to three different classesnucleoside analogue reverse transcriptase. The identification of drug resistance mutations was based on output from the stanford university hiv drug resistance database program. 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. Mutations conferring resistance to antiretroviral drugs are based on comparing gene sequences with corresponding consensus. 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.
Darunavir and tipranavir are two inhibitors that are active against multidrug resistant mdr hiv1 protease variants. 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. The data set, publicly available from the stanford hiv drug resistance database, was originally analyzed in rhee et al. Comparative evaluation of three computerized algorithms. Mutation frequencies at each position of protease or rt according to subtype. 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. Human immunodeficiency virus hiv replication is markedly inhibited by highly active antiretroviral drug combinations. The scientific goal is to determine which mutations of the human immunodeficiency virus type 1 hiv1 are associated with drug resistance. Apr 16, 2018 the identification of drug resistance mutations was based on output from the stanford university hiv drug resistance database program. Arv selection data comprising 168,662 protease, 178,122 rt and 21,549 integrase hiv 1 virus sequences from 187,693 persons. The levels of viral resistance to protease and reverse transcriptase inhibitors were predicted by the hivdb.
Major drug resistance mutations to hiv1 protease inhibitors. Current drug resistance genotyping methods are costly, optimized for subtype b virus. 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. Seq program of the stanford database for interpretation and simultaneously to virconet analysis on a. Previous treatment failure with a pi containing regimen may elicit resistance mutations, reducing pi susceptibility and.
Hiv drug resistance testing using the stanford university. Prediction of mutational tolerance in hiv1 protease and. Instead, we recommend the following current resources. Accessory mutations balance the marginal stability of the. Polymorphisms and resistance mutations in the protease and. 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. Hivseq accepts usersubmitted rt, protease, and integrase sequences or. It is critically important to understand the basis of this resistance for designing new drugs.
The data used in the study was derived from a publicly available, searchable database that shafer and his colleagues began at stanford in 1998. A curated database containing nearly all published hiv rt and protease sequences. First, the mutational tolerance of hiv 1 protease is well characterized. Virologic failure on antiretroviral therapy without hiv drug. The scientific goal is to determine which mutations of the human immunodeficiency virus type 1 hiv 1 are associated with drug resistance. New list of hiv mutations vital to tracking aids epidemic. Access to antiretroviral drugs for hiv 1 infection has increased in subsaharan africa ssa during the past few years.
Genotyperx hiv drug resistance database stanford university. In the reverse transcriptase rt gene, the most frequent mutations were found at codons 215 53%, 41 34%, and 67, 70, 184, and 210. Pdf knowledge integration of software for hiv drug. 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.
Crossclade simultaneous hiv drug resistance genotyping. Without a strong immune system, the body has trouble fighting off disease. Interdisciplinary initiatives program round 1 2000. Hivalg program hiv drug resistance database stanford university. For subtyping purposes, allthe nucleotide sequences were submitted to the.
Nucleotide sequences can be entered in fasta format or plain text. Mutation patterns of the reverse transcriptase and. Risk factors and outcomes for the q151m and t69 insertion. Hiv protease cleaves newly synthesized polyproteins namely, gag and gag pol at nine cleavage sites to create the mature protein. Crossclade simultaneous hiv drug resistance genotyping for. The software needed to implement these algorithms should remain stable to allow direct comparison between emerging algorithms and their component rules. The hivdb program on the web accepts usersubmitted protease and rt. 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. Dec 23, 2014 viral resistance to antiretroviral therapy threatens our best methods to control and prevent hiv infection. The sequences of the protease and reverse transcriptase genes were aligned clustalw and a phylogenetic tree was built mega 3 software. Sequences in fasta format or plain text can be pasted in the text box option a or uploaded option b. Human immunodeficiency virus reverse transcriptase and protease. The long term success of hivdb and other biomedical databases. Sep 09, 2011 in total, nine hiv 1 protease inhibitors have been approved by the u.
Access to antiretroviral drugs for hiv1 infection has increased in subsaharan africa ssa during the past few years. The current hiv 1 protease inhibitors are designed with a hydroxyl group. Known as the stanford hiv rt and protease sequence. We selected the data for which genotypic and phenotypic. 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. The program then returns a separate table for each observed mutation at that. Drug susceptibility data comprising 25,434 pi, 19,858 nrti, 11,548 nnrti and 4,606 ini susceptibility results from hiv 1 virus isolates. Background protease inhibitors pi are especially important in salvage therapy. Stanford hivdb program hivdb, the visible geneticsbayer diagnostics guidelines 6. More recently, the researchers have begun gathering resistance data on integrase inhibitors, the latest class of antiretroviral drugs to be introduced. To evaluate possible sample contamination maximum likelihood phylogenetic tree of hiv1 pol gene protease and reverse transcriptase from samples processed by.
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. Terms of use faqs hiv drug resistance database stanford. Download fullsize image genmol software is used for predicting hiv1 protease inhibitor pi resistance. Viral resistance to antiretroviral therapy threatens our best methods to control and prevent hiv infection.
One hundred and six hiv sequences derived from hiv. The data set, publicly available from the stanford hiv drug. Accurate interpretation of hiv drug resistance hivdr testing is challenging, yet important for patient care. 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. Previous treatment failure with a pi containing regimen may elicit resistance mutations, reducing pi susceptibility and limiting treatment options.
Accessory mutations balance the marginal stability of the hiv. Hiv gene sequence analysis for drug resistance studies. For subtyping purposes, allthe nucleotide sequences were submitted to the stanford database. Both the virus and the infection it causes are called hiv. Hiv human immunodeficiency virus is a virus that attacks the immune system, the bodys natural defense system. 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. Arv selection data comprising 168,662 protease, 178,122 rt and 21,549 integrase hiv1 virus sequences from 187,693 persons. For subtyping purposes, all the nucleotide sequences were submitted to the stanford database. The summary page describing a given peptidase can be reached by use of an index under its name, merops identifier or source organism. Drug resistance has sharply limited the effectiveness of hiv1 protease inhibitors in aids therapy.
Sep 12, 2012 human immunodeficiency virus type 1 hiv 1 protease inhibitors pis are the most potent class of drugs in antiretroviral therapies. Human immunodeficiency virus reverse transcriptase and. Risk factors and outcomes for the q151m and t69 insertion hiv. 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. Prevalence of transmitted drugresistance mutations and. The hiv reverse transcriptase and protease sequence database is an online relational.
Seq program of the stanford database for interpretation and simultaneously to virconet analysis on a commercial basis. 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. The higher barrier of darunavir and tipranavir resistance. It has been recompiled in 2008 listing 93 common mutations, after its initial mutation compilation in 2007 of 80 mutations. Structures of protease hiv drug resistance database stanford. All the studied strains were found to harbor accessory mutations in the protease gene. New stanford list of hiv mutations vital to tracking aids. 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 cannot cleave them, so they stay lodged in the active site, blocking the normal function of the enzyme. From the analysis of the hiv life cycle, one could con. Stanford university hiv drug resistance database website an online database created from published hiv sequences. The lanl hiv resistance mutation database is no longer maintained. Prevalence of reverse transcriptase and protease mutations.
With the increasing use of integrase inhibitors in firstline therapies, monitoring for integrase inhibitor. Extending hivdb functionality while securing data privacy. We compared genotyping interpretation, based on the stanford university hiv drug. Virologic failure on antiretroviral therapy without hiv. The hivdb system for hiv1 genotypic resistance interpretation. Mutations in the hiv1 genome are often associated with treatment failure as.
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. Database queries and references info relating to genotypetreatment correlations, genotype clinical outcome correlations, references, new submissions to database 2. First, the mutational tolerance of hiv1 protease is well characterized. 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. 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. 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. 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. Oct 24, 2012 accurate interpretation of hiv drug resistance hivdr testing is challenging, yet important for patient care. However, viral drug resistance to pis could emerge rapidly thus reducing the effectiveness of those drugs.
Hivdb criteria for classifying rt, protease and integrase mutations. A total of 1792 hiv1 protease sequences and their corresponding ic 50 values were retrieved from the stanford hiv drug resistance database. White blood cells are an important part of the immune system. Publicly available databases have revolutionized how biological research is. The stanford protease and rt database allows users to screen their own sequences for resistanceconferring mutations and compare them to stored sequences. Resistance genotyping was performed by using big dye terminator chemistry provided by the viroseq genotyping system. Hiv drug resistance interpretation algorithms will continue to evolve with the publication of new data and the introduction of new antiretroviral inhibitors. Current drug resistance genotyping methods are costly, optimized for subtype b virus, and primarily detect resistance mutations to protease and reverse transcriptase inhibitors. Rationale and uses of a public hiv drugresistance database. Comparative evaluation of three computerized algorithms for. Hiv1 protease cannot cleave them, so they stay lodged in the active site, blocking the normal function of the enzyme.
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