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Soo-Yon Rhee

Publications and source records attributed to Soo-Yon Rhee.

14 recordsLinked to original sources
PubMed2007

HIV-1 protease and reverse transcriptase mutations for drug resistance surveillance.

OBJECTIVES: Monitoring regional levels of transmitted HIV-1 resistance informs treatment guidelines and provides feedback on the success of HIV-1 prevention efforts. Surveillance programs for estimating the frequency of transmitted resistance are being developed in both industrialized and resource-poor countries. However, such programs will not produce comparable estimates unless a standardized list of drug-resistance mutations is used to define transmitted resistance. METHODS: In this paper, we outline considerations for developing a list of drug-resistance mutations for epidemiologic estimates of transmitted resistance. First, the mutations should cause or contribute to drug resistance and should develop in persons receiving antiretroviral therapy. Second, the mutations should not occur as polymorphisms in the absence of therapy. Third, the mutation list should be applicable to all group M subtypes. Fourth, the mutation list should be simple, unambiguous, and parsimonious. RESULTS: Applying these considerations, we developed a list of 31 protease inhibitor-resistance mutations at 14 protease positions, 31 nucleoside reverse transcriptase inhibitor-resistance mutations at 15 reverse transcriptase positions, and 18 non-nucleoside reverse transcriptase inhibitor-resistance mutations at 10 reverse transcriptase positions. CONCLUSIONS: This list, which should be updated regularly using the same or similar criteria, can be used for genotypic surveillance of transmitted HIV-1 drug resistance.

Anti-HIV Agents↗
PubMed2006

Genotypic predictors of human immunodeficiency virus type 1 drug resistance.

Understanding the genetic basis of HIV-1 drug resistance is essential to developing new antiretroviral drugs and optimizing the use of existing drugs. This understanding, however, is hampered by the large numbers of mutation patterns associated with cross-resistance within each antiretroviral drug class. We used five statistical learning methods (decision trees, neural networks, support vector regression, least-squares regression, and least angle regression) to relate HIV-1 protease and reverse transcriptase mutations to in vitro susceptibility to 16 antiretroviral drugs. Learning methods were trained and tested on a public data set of genotype-phenotype correlations by 5-fold cross-validation. For each learning method, four mutation sets were used as input features: a complete set of all mutations in > or =2 sequences in the data set, the 30 most common data set mutations, an expert panel mutation set, and a set of nonpolymorphic treatment-selected mutations from a public database linking protease and reverse transcriptase sequences to antiretroviral drug exposure. The nonpolymorphic treatment-selected mutations led to the best predictions: 80.1% accuracy at classifying sequences as susceptible, low/intermediate resistant, or highly resistant. Least angle regression predicted susceptibility significantly better than other methods when using the complete set of mutations. The three regression methods provided consistent estimates of the quantitative effect of mutations on drug susceptibility, identifying nearly all previously reported genotype-phenotype associations and providing strong statistical support for many new associations. Mutation regression coefficients showed that, within a drug class, cross-resistance patterns differ for different mutation subsets and that cross-resistance has been underestimated.

Drug Resistance, Viral↗
PubMed2006

HIV-1 pol mutation frequency by subtype and treatment experience: extension of the HIVseq program to seven non-B subtypes.

OBJECTIVE: HIVseq was developed in 2000 to make published data on the frequency of HIV-1 group M protease and reverse transcriptase (RT) mutations available in real time to laboratories and researchers sequencing these genes. Because most published protease and RT sequences belonged to subtype B, the initial version of HIVseq was based on this subtype. As additional non-B sequences from persons with well-characterized antiretroviral treatment histories have become available, the program has been extended to subtypes A, C, D, F, G, CRF01, and CRF02. METHODS: The latest frequency of each protease and RT mutation according to subtype and drug-class exposure was calculated using published sequences in the Stanford HIV RT and Protease Sequence Database. Each mutation was hyperlinked to published reports of viruses containing the mutation. RESULTS: As of September 2005, the mean number of protease sequences per non-B subtype was 534 from protease inhibitor-naive persons and 133 from protease inhibitor-treated persons, representing 13.2% and 2.3%, respectively, of the data available for subtype B. The mean number of RT sequences per non-B subtype was 373 from RT inhibitor-naive persons and 288 from RT inhibitor-treated persons, representing 17.9% and 3.8%, respectively, of the data available for subtype B. CONCLUSIONS: HIVseq allows users to examine protease and RT mutations within the context of previously published sequences of these genes. The publication of additional non-B protease and RT sequences from persons with well-characterized treatment histories, however, will be required to perform the same types of analysis possible with the much larger number of subtype B sequences.

Base Sequence↗
PubMed2006

N88D facilitates the co-occurrence of D30N and L90M and the development of multidrug resistance in HIV type 1 protease following nelfinavir treatment failure.

Nelfinavir was once one of the most commonly used protease inhibitors (PIs). To investigate the genetic mechanisms of multidrug resistance in protease isolates with the primary nelfinavir resistance mutation D30N, we analyzed patterns of protease mutations in 582 viruses with D30N from 460 persons undergoing HIV-1 genotypic resistance testing at Stanford University Hospital from 1997 to 2005. Three patterns of mutational associations were identified. First, D30N was positively associated with N88D but negatively associated with N88S. Second, D30N and L90M were negatively associated except in the presence of N88D, which facilitated the co-occurrence of D30N and L90M. Third, D30N+N88D+L90M formed a stable genetic backbone for the accumulation of additional protease inhibitor (PI) resistance mutations. In 16 patients having isolates with more than one combination of mutations at positions 30, 88, and 90, all exhibited one of the steps in the following progression: D30N-->D30N+N88D-->D30N+N88D+L90M-->D30N+N88D+L90M+(L33F+/-I84V or M46I/L+/-I54V). Although nelfinavir is now used less frequently than other PIs, the well-delineated mutational pathway we describe is likely to influence patterns of cross-resistance in viruses from persons who experience virologic failure while receiving this PI.

Base Sequence↗
PubMed2005

HIV-1 Protease and reverse-transcriptase mutations: correlations with antiretroviral therapy in subtype B isolates and implications for drug-resistance surveillance.

Background. It is important, for drug-resistance surveillance, to identify human immunodeficiency virus type 1 (HIV-1) strains that have undergone antiretroviral drug selection.Methods. We compared the prevalence of protease and reverse-transcriptase (RT) mutations in HIV-1 sequences from persons with and without previous treatment with protease inhibitors (PIs), nucleoside RT inhibitors (NRTIs), and nonnucleoside RT inhibitors (NNRTIs). Treatment-associated mutations in protease isolates from 5867 persons and RT isolates from 6247 persons were categorized by whether they were polymorphic (prevalence, >0.5%) in untreated individuals and whether they were established drug-resistance mutations. New methods were introduced to minimize misclassification from transmitted resistance, population stratification, sequencing artifacts, and multiple hypothesis testing.Results. Some 36 established and 24 additional nonpolymorphic protease mutations at 34 positions were related to PI treatment, 21 established and 22 additional nonpolymorphic RT mutations at 24 positions with NRTI treatment, and 15 established and 11 additional nonpolymorphic RT mutations at 15 positions with NNRTI treatment. In addition, 11 PI-associated and 1 NRTI-associated established mutations were polymorphic in viruses from untreated persons.Conclusions. Established drug-resistance mutations encompass only a subset of treatment-associated mutations; some of these are polymorphic in untreated persons. In contrast, nonpolymorphic treatment-associated mutations may be more sensitive and specific markers of transmitted HIV-1 drug resistance.

Anti-HIV Agents↗
PubMed2005

Panel of prototypical infectious molecular HIV-1 clones containing multiple nucleoside reverse transcriptase inhibitor resistance mutations.

We have created a panel of recombinant HIV-1 infectious clones containing common patterns of reverse transcriptase (RT) mutations responsible for resistance to each of the currently available nucleoside reverse transcriptase inhibitors (NRTI), and we have submitted the panel to the National Institutes of Health AIDS Research and Reference Reagent Programme. Testing the activity of new antiretroviral compounds against this panel of drug-resistant clones will determine their relative activity against many clinically relevant NRTI-resistant viruses.

Clone Cells↗
PubMed2005

Comparison of the precision and sensitivity of the Antivirogram and PhenoSense HIV drug susceptibility assays.

OBJECTIVE: Although 2 widely used susceptibility assays have been developed, their precision and sensitivity have not been assessed. DESIGN AND METHODS: To assess the precision of the Antivirogram and PhenoSense assays, we examined susceptibility results of HIV-1 isolates lacking drug resistance mutations and containing matching patterns of drug resistance mutations. To assess sensitivity, we determined for each assay the proportion of isolates with common patterns of matching drug resistance mutations having reductions in susceptibility greater than those in isolates without drug resistance mutations. RESULTS: We analyzed protease inhibitor (PI) susceptibility results obtained by the Antivirogram assay for 293 isolates and by the PhenoSense assay for 300 isolates. We analyzed reverse transcriptase (RT) inhibitor susceptibility results obtained by the Antivirogram assay for 202 isolates and by the PhenoSense assay for 126 isolates. For wild-type and mutant isolates, the median absolute deviance of the fold resistance of nucleoside RT inhibitor susceptibility results was significantly lower for the PhenoSense assay than for the Antivirogram assay. The PhenoSense assay was also significantly more likely than the Antivirogram assay to detect resistance to abacavir, didanosine, and stavudine in isolates with the common drug resistance mutations M41L, M184V, and T215Y (+/-L210W). We found no significant differences between the 2 assays for detecting PI and nonnucleoside RT inhibitor resistance. CONCLUSION: The PhenoSense assay is more precise than the Antivirogram assay and superior at detecting resistance to abacavir, didanosine, and stavudine.

Acquired Immunodeficiency Syndrome↗
PubMed2004

Association of a novel human immunodeficiency virus type 1 protease substrate cleft mutation, L23I, with protease inhibitor therapy and in vitro drug resistance.

We observed a previously uncharacterized mutation in the protease substrate cleft, L23I, in 31 of 4,303 persons undergoing human immunodeficiency virus type 1 genotypic resistance testing. In combination with V82I, L23I was associated with a sevenfold reduction in nelfinavir susceptibility and a decrease in replication capacity. In combination with other drug resistance mutations, L23I was associated with multidrug resistance and a compensatory increase in replication capacity.

Drug Resistance, Viral↗
PubMed2004

Distribution of human immunodeficiency virus type 1 protease and reverse transcriptase mutation patterns in 4,183 persons undergoing genotypic resistance testing.

In a sample of 6,156 sequences from 4,183 persons, the top 30 patterns of protease inhibitor, nucleoside reverse transcriptase (RT) inhibitor, and nonnucleoside RT inhibitor mutations accounted for 55, 46, and 66%, respectively, of sequences with drug resistance mutations. Characterization of the phenotypic and clinical significance of these common patterns may lead to improved treatment recommendations for a large proportion of patients for whom antiretroviral therapy is failing.

Drug Resistance, Viral↗
PubMed2004

Sequencing-based detection of low-frequency human immunodeficiency virus type 1 drug-resistant mutants by an RNA/DNA heteroduplex generator-tracking assay.

Drug-resistant viruses may be present as minority variants during early treatment failures or following discontinuation of failed antiretroviral regimens. A limitation of the traditional direct PCR population sequencing method is its inability to detect human immunodeficiency virus type 1 (HIV-1) variants present at frequencies lower than 20%. A drug resistance genotyping assay based on the isolation and DNA sequencing of minority HIV protease variants is presented here. A multiple-codon-specific heteroduplex generator probe was constructed to improve the separation of HIV protease genes varying in sequence at 12 codons associated with resistance to protease inhibitors. Using an RNA molecule as probe allowed the simple sequencing of protease variants isolated as RNA/DNA heteroduplexes with different electrophoretic mobilities. The protease gene RNA heteroduplex generator-tracking assay (RNA-HTA) was tested on plasma quasispecies from 21 HIV-1-infected persons in whom one or more protease resistance mutations emerged during therapy or following initiation of salvage regimens. In 11 of 21 cases, RNA-HTA testing of virus from the first episode of virologic failure identified protease resistance mutations not seen by population-based PCR sequencing. In 8 of these 11 cases, all of the low-frequency drug resistance mutations detected exclusively by RNA-HTA during the first episode became detectable by population-based PCR sequencing at the later time point. Distinct sets of protease mutations could be linked on different genomes in patients with high-frequency protease gene lineages. The enhanced detection of minority drug resistance variants using a sequencing-based assay may improve the efficacy of genotype-assisted salvage therapies.

Base Sequence↗
PubMed2003

Lack of detectable human immunodeficiency virus type 1 superinfection during 1072 person-years of observation.

We examined consecutive protease (PR) and reverse transcriptase (RT) sequences from human immunodeficiency virus (HIV) type 1-infected individuals, to distinguish changes resulting from sequence evolution due to possible superinfection. Between July 1997 and December 2001, >/=2 PR and RT samples from 718 persons were sequenced at Stanford University Hospital. Thirty-seven persons had highly divergent sequence pairs characterized by a nucleotide distance of >4.5% in PR or >3.0% in RT. In 16 of 37 sequence pairs, divergence resulted from the loss of mutations during a treatment interruption or from the gain of mutations with reinstitution of treatment. tat and/or gag sequencing of HIV-1 from cryopreserved plasma samples could be performed on 15 of the 21 divergent isolate pairs from persons without a treatment interruption. The sequences of these genes, unaffected by selective drug pressure, were monophyletic. Although HIV-1 PR and RT genes from treated persons may become highly divergent, these changes usually are the result of sequence evolution, rather than superinfection.

California↗
PubMed2003

Human immunodeficiency virus reverse transcriptase and protease sequence database.

The HIV reverse transcriptase and protease sequence database is an on-line relational database that catalogues evolutionary and drug-related sequence variation in the human immunodeficiency virus (HIV) reverse transcriptase (RT) and protease enzymes, the molecular targets of antiretroviral therapy (http://hivdb.stanford.edu). The database contains a compilation of nearly all published HIV RT and protease sequences, including submissions to GenBank, sequences published in journal articles and sequences of HIV isolates from persons participating in clinical trials. Sequences are linked to data about the source of the sequence, the antiretroviral drug treatment history of the person from whom the sequence was obtained and the results of in vitro drug susceptibility testing. Sequence data on two new molecular targets of HIV drug therapy--gp41 (cell fusion) and integrase--will be added to the database in 2003.

Amino Acid Sequence↗
PubMed2003

Protease and reverse transcriptase mutation patterns in HIV type 1 isolates from heavily treated persons: comparison of isolates from Northern California with isolates from other regions.

We compared HIV-1 subtype B reverse transcriptase (RT) and protease mutation patterns in isolates from heavily treated persons in Northern California with those from persons described in the published literature predominantly from other parts of the United States and Europe. There were few differences in the prevalence of single, double, and triple mutations between the two sets of sequences. More complex patterns of mutations could be characterized by clustering the sequences into eight groups of RT sequences and nine groups of protease sequences according to the presence of known drug-resistance mutations. This clustering accounted for 63% of the variation at RT inhibitor-resistance positions and 68% of the variation at protease inhibitor-resistance positions. The majority of clusters contained Northern California and literature sequences in similar proportions.

California↗