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

Rhee, Soo-Yon; Kantor, Rami; Katzenstein, David; Camacho, Ricardo Jorge; Morris, Lynn; Sirivichayakul, Sunee; Jørgensen, Louise L.B.; Brígido, Luis Fernando de Macedo; Schapiro, Jonathan; Shafer, Robert W.

doi:10.1097/01.aids.0000216363.36786.2b

Cited by 80 publications

(71 citation statements)

References 11 publications

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“…The 106M mutation appears in the same studies at least three times as often as the 106A mutation in the same cohorts. In addition, according to the Stanford University Drug Resistance database, only 1.5% of all subtype C HIV sequences obtained from individuals who received at least one NNRTI contained the 106A mutation, while 11% had the 106M mutation (37). The fitness data can help explain why the 106M mutation is favored over the 106A mutation in the clinical setting.…”

Section: Discussionmentioning

confidence: 99%

Replicative Fitness Costs of Nonnucleoside Reverse Transcriptase Inhibitor Drug Resistance Mutations on HIV Subtype C

Armstrong

Lee

Essex

2011

Antimicrob Agents Chemother

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Single-dose nevirapine (NVP) is quite effective in preventing transmission of the human immunodeficiency virus (HIV) from mother to child; however, many women develop resistance to NVP in this setting. Comparing outcomes of clinical studies reveals an increased amount of resistance in subtype C relative to that in other subtypes. This study investigates how nonnucleoside reverse transcriptase inhibitor (NNRTI) drug resistance mutations of subtype C affect replication capacity. The 103N, 106A, 106M, 181C, 188C, 188L, and 190A drug resistance mutations were placed in a reverse transcriptase (RT) that matches the consensus subtype C sequence as well as the HXB2 RT, as a subtype B reference. The replicative fitness of each mutant was compared with that of the wild type in a head-to-head competition assay. The 106A mutant of subtype C would not grow in the competition assay, making it the weakest virus tested. The effect of the 106M mutation was weaker than those of the 181C and 188C mutations in the consensus C RT, but in subtype B, this difference was not seen. To see if the 106A mutation in a different subtype C background would have a different replicative profile, the same NNRTI resistance mutations were added to the MJ4 RT, a reference subtype C molecular clone. In the context of MJ4 RT, the 106A mutant was not the only mutant that showed poor replicative fitness; the 106M, 188C, and 190A mutants also failed to replicate. These results suggest that NNRTIs may be a cost-effective alternative for salvage therapy if deleterious mutations are present in a subtype C setting.The emergence of drug-resistant mutants is common among HIV-infected patients undergoing antiviral therapy. Clinically, the standard practice is to drop the antiviral to which the resistance has developed from the treatment regimen in such drug failure cases. However, a notable exception to this is the continuing use of lamivudine (3TC) as a salvage regimen because the 184V mutation linked to 3TC treatment has decreased replication ability relative to that of the wild type (WT) in subtype B (7). Mechanistically, Back et al. (2) found that the 184V mutant is less processive than wild-type RT under conditions of limiting deoxynucleoside triphosphates (dNTPs), and in primary lymphoid cells, the mutant is less fit than wildtype virus. These studies were extended further in vivo by Paredes et al. (35), who looked at multidrug-resistant virus from patients who were ending 3TC treatment. They used an allele-specific PCR assay to track the reversion of the M184V sequence and found that there was a fitness cost of 4 to 8% for the 184V mutation compared to that of the viral sequence that grew without 3TC drug pressure. Taken together, these studies illustrate how clinical management of HIV-infected patients can benefit from the study of the fitness cost of HIV drugresistant mutants.The use of antiretroviral drugs is increasing in the developing world. In particular, the use of single-dose nevirapine (NVP) has been shown to be an effective means of mitigat...

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Section: Discussionmentioning

confidence: 99%

Replicative Fitness Costs of Nonnucleoside Reverse Transcriptase Inhibitor Drug Resistance Mutations on HIV Subtype C

Armstrong

Lee

Essex

2011

Antimicrob Agents Chemother

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“…HIVseq outputs a table that shows the prevalence of the mutation in viruses belonging to group M subtypes A, B, C, D, F and G, and CRFs 01_AE and 02_AG according to ARV treatment [8]. HIVseq, therefore, identifies subtype-specific polymorphisms and ARV resistance mutations.…”

Section: Related Programs and Featuresmentioning

confidence: 99%

The HIVdb System for HIV-1 Genotypic Resistance Interpretation

Tang

Liu

Shafer³

2012

Intervirology

121

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The Stanford HIV Drug Resistance Database hosts a freely available online genotypic resistance interpretation system called HIVdb to help clinicians and laboratories interpret HIV-1 genotypic resistance tests. These tests are designed to assess susceptibility to nucleoside and nonnucleoside reverse transcriptase inhibitors (NRTI and NNRTI), protease inhibitors and integrase inhibitors. The HIVdb genotypic resistance interpretation system output consists of (1) a list of penalty scores for each antiretroviral (ARV) resistance mutation in a submitted sequence, (2) estimates of decreased NRTI, NNRTI, protease and integrase inhibitor susceptibility, and (3) comments about each ARV resistance mutation in the submitted sequence. The application’s strengths are its convenience for submitting sequences, its quality control analysis, its transparency and its extensive comments. The Sierra Web service is an extension that enables laboratories analyzing many sequences to individualize the format of their results. The algorithm specification interface compiler makes it possible for HIVdb to provide results using a variety of different HIV-1 genotypic resistance interpretation algorithms.

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“…Using IRR, we separately analyzed each subtype's samples, since C and B subtypes display different resistance mutation patterns (Grossman et al, 2004;Kantor et al, 2005;Rhee et al, 2006).…”

Section: Methodsmentioning

confidence: 99%

Using Iterative Ridge Regression to Explore Associations Between Conditioned Variables

Bar-Yaakov

Grossman

Intrator

2012

Journal of Computational Biology

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We address a specific case of joint probability mapping, where the information presented is the probabilistic associations of random variables under a certain condition variable (conditioned associations). Bayesian and dependency networks graphically map the joint probabilities of random variables, though both networks may identify associations that are independent of the condition (background associations). Since the background associations have the same topological features as conditioned associations, it is difficult to discriminate between conditioned and non-conditioned associations, which results in a major increase in the search space. We introduce a modification of the dependency network method, which produces a directed graph, containing only condition-related associations. The graph nodes represent the random variables and the graph edges represent the associations that arise under the condition variable. This method is based on ridge-regression, where one can utilize a numerically robust and computationally efficient algorithm implementation. We illustrate the method's efficiency in the context of a medically relevant process, the emergence of drug-resistant variants of human immunodeficiency virus (HIV) in drug-treated, HIV-infected people. Our mapping was used to discover associations between variants that are conditioned by the initiation of a particular drug treatment regimen. We have demonstrated that our method can recover known associations of such treatment with selected resistance mutations as well as documented associations between different mutations. Moreover, our method revealed novel associations that are statistically significant and biologically plausible.

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

Cited by 80 publications

References 11 publications

Replicative Fitness Costs of Nonnucleoside Reverse Transcriptase Inhibitor Drug Resistance Mutations on HIV Subtype C

Replicative Fitness Costs of Nonnucleoside Reverse Transcriptase Inhibitor Drug Resistance Mutations on HIV Subtype C

The HIVdb System for HIV-1 Genotypic Resistance Interpretation

Using Iterative Ridge Regression to Explore Associations Between Conditioned Variables

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