Changing Patterns in the Selection of Viral Mutations among Patients Receiving Nucleoside and Nucleotide Drug Combinations Directed against Human Immunodeficiency Virus Type 1 Reverse Transcriptase

Wainberg, Mark A.; Brenner, Bluma G.; Turner, Dan

doi:10.1128/aac.49.5.1671-1678.2005

Cited by 21 publications

(15 citation statements)

References 35 publications

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“…For example, transmission of resistance in the era of mono or dual therapy with nucleoside reverse transcriptase inhibitors (NRTIs) may have been predominantly due to thymidine analogue associated resistance mutations such as M41L and T215Y/F [5 ]. In contrast, following the introduction of nonnucleoside reverse transcriptase inhibitors (NNRTIs), there was a marked increase in the incidence of NNRTI-associated resistance observed in treatment of naïve patients [6 ].…”

Section: Levels Of Transmitted Drug Resistancementioning

confidence: 99%

Stability of transmitted drug-resistant HIV-1 species

Cane

2005

Current Opinion in Infectious Diseases

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Section: Levels Of Transmitted Drug Resistancementioning

confidence: 99%

Stability of transmitted drug-resistant HIV-1 species

Cane

2005

Current Opinion in Infectious Diseases

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“…Interaction between mutations selected by both drugs has been reported. Lowlevel resistance to AZT can be reversed with the emergence of the 184V mutation (Wainberg et al, 2005). This resensitization effect may explain why this dual NRTI backbone has been found to be both potent and slow in resistance development.…”

Section: Introductionmentioning

confidence: 96%

Resistance pathways of human immunodeficiency virus type 1 against the combination of zidovudine and lamivudine

Theys

Deforche

Libin

et al. 2010

Journal of General Virology

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A better understanding of human immunodeficiency virus type 1 drug-resistance evolution under the selective pressure of combination treatment is important for the design of long-term effective treatment strategies. We applied Bayesian network learning to sequences from patients treated with the reverse transcriptase inhibitor combination of zidovudine (AZT) and lamivudine (3TC) to identify the role of many treatment-selected mutations in the development of resistance. Based on the Bayesian network structure, an in vivo fitness landscape was built, reflecting the necessary selective pressure under treatment, to evolve naive sequences to sequences obtained from patients treated with the combination. This landscape, combined with an evolutionary model, was used to predict resistance evolution in longitudinal sequence pairs. In our analysis, mutations 41L, 70R, 184V and 215F/Y were identified as major resistance mutations to the combination of AZT and 3TC, as they were associated directly with treatment experience. The network also suggested a possible role in resistance development for a number of novel mutations. Estimated fitness, using the landscape, correlated significantly with in vitro resistance phenotype in genotypephenotype pairs (R 2 50.70). Variation in predicted evolution under selective pressure correlated significantly with observed in vivo evolution during AZT plus 3CT treatment. In conclusion, we confirmed current knowledge on resistance development to the combination of AZT and 3CT, but additional novel mutations were identified. Moreover, a model to predict resistance evolution during AZT and 3CT treatment has been built and validated.

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“…In RT, a change at position 184 from methionine to valine results in an increase in FC for 3TC [11], [12] and FTC [13] while it decreases the FC for AZT, d4T and TDF [14]. This effect was observed with both types of backbone as shown in Fig.…”

Section: Resultsmentioning

confidence: 88%

A Synthetic HIV-1 Subtype C Backbone Generates Comparable PR and RT Resistance Profiles to a Subtype B Backbone in a Recombinant Virus Assay

Nauwelaers¹,

Houtte²,

Winters³

et al. 2011

PLoS ONE

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In order to determine phenotypic protease and reverse transcriptase inhibitor-associated resistance in HIV subtype C virus, we have synthetically constructed an HIV-1 subtype C (HIV-1-C) viral backbone for use in a recombinant virus assay. The in silico designed viral genome was divided into 4 fragments, which were chemically synthesized and joined together by conventional subcloning. Subsequently, gag-protease-reverse-transcriptase (GPRT) fragments from 8 HIV-1 subtype C-infected patient samples were RT-PCR-amplified and cloned into the HIV-1-C backbone (deleted for GPRT) using In-Fusion reagents. Recombinant viruses (1 to 5 per patient sample) were produced in MT4-eGFP cells where cyto-pathogenic effect (CPE), p24 and Viral Load (VL) were monitored. The resulting HIV-1-C recombinant virus stocks (RVS) were added to MT4-eGFP cells in the presence of serial dilutions of antiretroviral drugs (PI, NNRTI, NRTI) to determine the fold-change in IC50 compared to the IC50 of wild-type HIV-1 virus. Additionally, viral RNA was extracted from the HIV-1-C RVS and the amplified GPRT products were used to generate recombinant virus in a subtype B backbone. Phenotypic resistance profiles in a subtype B and subtype C backbone were compared. The following observations were made: i) functional, infectious HIV-1 subtype C viruses were generated, confirmed by VL and p24 measurements; ii) their rate of infection was slower than viruses generated in the subtype B backbone; iii) they did not produce clear CPE in MT4 cells; and iv) drug resistance profiles generated in both backbones were very similar, including re-sensitizing effects like M184V on AZT.

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Changing Patterns in the Selection of Viral Mutations among Patients Receiving Nucleoside and Nucleotide Drug Combinations Directed against Human Immunodeficiency Virus Type 1 Reverse Transcriptase

Cited by 21 publications

References 35 publications

Stability of transmitted drug-resistant HIV-1 species

Stability of transmitted drug-resistant HIV-1 species

Resistance pathways of human immunodeficiency virus type 1 against the combination of zidovudine and lamivudine

A Synthetic HIV-1 Subtype C Backbone Generates Comparable PR and RT Resistance Profiles to a Subtype B Backbone in a Recombinant Virus Assay

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