Resistance Mutation

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Robert W Shafer - One of the best experts on this subject based on the ideXlab platform.

  • Q148N, a Novel Integrase Inhibitor Resistance Mutation Associated with Low-Level Reduction in Elvitegravir Susceptibility.
    AIDS research and human retroviruses, 2016
    Co-Authors: Vici Varghese, Benjamin A Pinsky, Darvin Scott Smith, Daniel B. Klein, Robert W Shafer
    Abstract:

    The integrase strand transfer inhibitor (INSTI)-Resistance Mutations Q148H/K/R are arguably the most important INSTI-Resistance Mutations as they represented the first step to high-level dolutegravir cross-Resistance. We describe an individual with transmitted four-class drug Resistance whose virus sequence had the previously uncharacterized Mutation Q148N. Infectious molecular HIV-1 clones containing Q148N alone and in combination with G140S demonstrated ∼2.4-4.5 reduced elvitegravir susceptibility depending on the virus's genetic context but retained susceptibility to raltegravir and dolutegravir. This level of reduced elvitegravir susceptibility is lower than that observed with Q148H/K/R and in fact the infected individual responded to an initial treatment regimen containing tenofovir/emtricitabine/elvitegravir/cobicistat. Q148N was associated with a higher replication capacity than Q148H, suggesting that this Mutation may be more fit in the absence of selective INSTI therapy.

  • detection of minority populations of hiv 1 expressing the k103n Resistance Mutation in patients failing nevirapine
    Journal of Acquired Immune Deficiency Syndromes, 2005
    Co-Authors: Denise Lecossier, Nancy S. Shulman, Robert W Shafer, Laurence Morandjoubert, Veronique Joly, Andrew R Zolopa, Francois Clavel, Allan J Hance
    Abstract:

    Summary: Salvage therapy with efavirenz is often ineffective in patients having failed nevirapine treatment, even when Mutations associated with efavirenz Resistance are not detected by standard population-based genotyping. The presence of minority viral populations expressing efavirenz cross-Resistance could explain these observations, and such populations were sought in plasma from patients failing nevirapine for whom genotyping revealed the presence of the Y181C Mutation (usually associated with limited efavirenz cross-Resistance) but not the K103N Mutation (which produces high-level efavirenz Resistance). Viral populations expressing K103N (>1% total virus) were detected by sequence-selective polymerase chain reaction in 4 of 16 patients failing nevirapine, although, in retrospect, the Mutation was not perceptible in the original genotype in only 2 cases. Both patients with detectable K103N Mutations whoreceived efavirenz failed treatment, and virus expressing K103N emerged. Four of 5 patients without detectable K103N Mutations also failed efavirenz, associated with the emergence of nonnucleoside reverse transcriptase Mutations that included K103N in 2 cases. The emergence of a minority viral population expressing K103N was identified in 1 patient from a separate study group subsequent to discontinuing treatment with nevirapine. These findings support the idea that minority viral populations with distinct Resistance genotypes, although undetectable by standard genotyping, can contribute to the failure of salvage regimens.

  • interlaboratory comparison of sequence specific pcr and ligase detection reaction to detect a human immunodeficiency virus type 1 drug Resistance Mutation the aids clinical trials group virology committee drug Resistance working group
    Journal of Clinical Microbiology, 1996
    Co-Authors: Robert W Shafer, Mark A Winters, Douglas L Mayers, Anthony J Japour, Daniel R Kuritzkes, Owen S Weislow, F White, Alejo Erice, Kim J Sannerud, Astrid K N Iversen
    Abstract:

    Sequence-specific PCR was used in six laboratories and a ligase detection reaction was used in one laboratory to detect the zidovudine-Resistance Mutation at codon 215 of human immunodeficiency virus type 1 (HIV-1) reverse transcriptase DNA. The genotypes of 27 different clinical samples, including cultured HIV-1 isolates, peripheral blood mononuclear cells, and plasma, were correctly identified by 140 of 154 (91%) assays. The sensitivity for detecting a Mutation was 96% for HIV-1 reverse transcriptase DNA clone mixtures containing 30% mutant DNA and 62% for mixtures containing 6% mutant DNA.

  • combination therapy with zidovudine and didanosine selects for drug resistant human immunodeficiency virus type 1 strains with unique patterns of pol gene Mutations
    The Journal of Infectious Diseases, 1994
    Co-Authors: Robert W Shafer, Michael J Kozal, Mark A Winters, Astrid K N Iversen, David Katzenstein, Margaret V Ragni, William A Meyer, Phalquni Gupta, Suraiya Rasheed, Robert W. Coombs
    Abstract:

    Drug Resistance conferred by specific human immunodeficiency virus type 1 (HIV-1) pol gene Mutations has been associated with clinical progression in HIV-infected patients receiving anti-retroviral therapy. This study examined drug susceptibilities and pol Mutations of HIV-1 strains from patients treated for I year with zidovudine, didanosine (ddI), or zidovudine and ddI. Ten (42%) of 24 patients receiving combination therapy versus 8/26 (31%) receiving only zidovudine had HIV-1 strains with phenotypic zidovudine Resistance or a zidovudine Resistance pol Mutation at codon 215 (P=.6). In contrast, a ddI Resistance Mutation at codon 74 was less common among patients receiving combination therapy (2/24) than among those receiving ddI only (17/26; P<.001)

  • combination therapy with zidovudine and didanosine selects for drug resistant human immunodeficiency virus type 1 strains with unique patterns of pol gene Mutations
    The Journal of Infectious Diseases, 1994
    Co-Authors: Robert W Shafer, Michael J Kozal, Mark A Winters, Astrid K N Iversen, David Katzenstein, Margaret V Ragni, William A Meyer, Phalquni Gupta, Suraiya Rasheed, Robert W. Coombs
    Abstract:

    Drug Resistance conferred by specific human immunodeficiency virus type 1 (HIV-1) pol gene Mutations has been associated with clinical progression in HIV-infected patients receiving anti-retroviral therapy. This study examined drug susceptibilities and pol Mutations of HIV-1 strains from patients treated for 1 year with zidovudine, didanosine (ddI), or zidovudine and ddI. Ten (42%) of 24 patients receiving combination therapy versus 8/26 (31%) receiving only zidovudine had HIV-1 strains with phenotypic zidovudine Resistance or a zidovudine Resistance pol Mutation at codon 215 (P = .6). In contrast, a ddI Resistance Mutation at codon 74 was less common among patients receiving combination therapy (2/24) than among those receiving ddI only (17/26; P < .001). Two patients receiving combination therapy developed Resistance to zidovudine and ddI; they had HIV strains with amino acid Mutations at codons 62, 75, 77, 116, and 151. Combination therapy with zidovudine and ddI selects for zidovudine-resistant HIV-1 strains lacking a ddI Resistance Mutation and for multidrug-resistant strains containing novel pol Mutations.

David Katzenstein - One of the best experts on this subject based on the ideXlab platform.

  • human immunodeficiency virus 1 sequence changes and drug Resistance Mutation among virologic failures of lopinavir ritonavir monotherapy aids clinical trials group protocol a5230
    Open Forum Infectious Diseases, 2016
    Co-Authors: Saran Vardhanabhuti, David Katzenstein, John Bartlett, Nagalingeswaran Kumarasamy, Carole L Wallis
    Abstract:

    Background. The mechanism of virologic failure (VF) of lopinavir/ritonavir (LPV/r) monotherapy is not well understood. We assessed sequence changes in human immunodeficiency virus-1 reverse-transcriptase (RT) and protease (PR) regions. Methods. Human immunodeficiency virus-1 pol sequences from 34 participants who failed second-line LPV/r monotherapy were obtained at study entry (SE) and VF. Sequence changes were evaluated using phylogenetic analysis and hamming distance. Results. Human immunodeficiency virus-1 sequence change was higher over drug Resistance Mutation (DRM) sites (median genetic distance, 2.2%; Q1 to Q3, 2.1%–2.5%) from SE to VF compared with non-DRM sites (median genetic distance, 1.3%; Q1 to Q3, 1.0%–1.4%; P < .0001). Evolution over DRM sites was mainly driven by changes in the RT (median genetic distance, 2.7%; Q1 to Q3, 2.2%–3.2%) compared with PR (median genetic distance, 1.1%; Q1 to Q3, 0.0%–1.1%; P < .0001). Most RT DRMs present at SE were lost at VF. At VF, 19 (56%) and 26 (76%) were susceptible to efavirenz/nevirapine and etravirine (ETV)/rilpivirine (RPV), respectively, compared with 1 (3%) and 12 (35%) at SE. Participants who retained nonnucleoside reverse-transcriptase inhibitor (NNRTI) DRMs and those without evolution of LPV/r DRMs had significantly shorter time to VF. Conclusions. The selection of LPV/r DRMs in participants with longer time to VF suggests better adherence and more selective pressure. Fading NNRTI Mutations and an increase in genotypic susceptibility to ETV and RPV could allow for the reuse of NNRTI. Further studies are warranted to understand mechanisms of PR failure.

  • nucleic acid template and the risk of a pcr induced hiv 1 drug Resistance Mutation
    PLOS ONE, 2010
    Co-Authors: Vici Varghese, David Katzenstein, Rajin Shahriar, Farbod Babrzadeh, Baback Gharizadeh, Elijah Wang, Michael H Bachmann, Svetlana Jean M Mappala, Jeffrey W Fessel, Seble Kassaye
    Abstract:

    Author(s): Varghese, Vici; Wang, Elijah; Babrzadeh, Farbod; Bachmann, Michael H; Shahriar, Rajin; Liu, Tommy; Mappala, Svetlana Jean M; Gharizadeh, Baback; Fessel, W Jeffrey; Katzenstein, David; Kassaye, Seble; Shafer, Robert W | Abstract: The HIV-1 nucleoside RT inhibitor (NRTI)-Resistance Mutation, K65R confers intermediate to high-level Resistance to the NRTIs abacavir, didanosine, emtricitabine, lamivudine, and tenofovir; and low-level Resistance to stavudine. Several lines of evidence suggest that K65R is more common in HIV-1 subtype C than subtype B viruses.We performed ultra-deep pyrosequencing (UDPS) and clonal dideoxynucleotide sequencing of plasma virus samples to assess the prevalence of minority K65R variants in subtype B and C viruses from untreated individuals. Although UDPS of plasma samples from 18 subtype C and 27 subtype B viruses showed that a higher proportion of subtype C viruses contain K65R (1.04% vs. 0.25%; pl0.001), limiting dilution clonal sequencing failed to corroborate its presence in two of the samples in which K65R was present in g1.5% of UDPS reads. We therefore performed UDPS on clones and site-directed mutants containing subtype B- and C-specific patterns of silent Mutations in the conserved KKK motif encompassing RT codons 64 to 66 and found that subtype-specific nucleotide differences were responsible for increased PCR-induced K65R Mutation in subtype C viruses.This study shows that the RT KKK nucleotide template in subtype C viruses can lead to the spurious detection of K65R by highly sensitive PCR-dependent sequencing techniques. However, the study is also consistent with the subtype C nucleotide template being inherently responsible for increased polymerization-induced K65R Mutations in vivo.

  • combination therapy with zidovudine and didanosine selects for drug resistant human immunodeficiency virus type 1 strains with unique patterns of pol gene Mutations
    The Journal of Infectious Diseases, 1994
    Co-Authors: Robert W Shafer, Michael J Kozal, Mark A Winters, Astrid K N Iversen, David Katzenstein, Margaret V Ragni, William A Meyer, Phalquni Gupta, Suraiya Rasheed, Robert W. Coombs
    Abstract:

    Drug Resistance conferred by specific human immunodeficiency virus type 1 (HIV-1) pol gene Mutations has been associated with clinical progression in HIV-infected patients receiving anti-retroviral therapy. This study examined drug susceptibilities and pol Mutations of HIV-1 strains from patients treated for I year with zidovudine, didanosine (ddI), or zidovudine and ddI. Ten (42%) of 24 patients receiving combination therapy versus 8/26 (31%) receiving only zidovudine had HIV-1 strains with phenotypic zidovudine Resistance or a zidovudine Resistance pol Mutation at codon 215 (P=.6). In contrast, a ddI Resistance Mutation at codon 74 was less common among patients receiving combination therapy (2/24) than among those receiving ddI only (17/26; P<.001)

  • combination therapy with zidovudine and didanosine selects for drug resistant human immunodeficiency virus type 1 strains with unique patterns of pol gene Mutations
    The Journal of Infectious Diseases, 1994
    Co-Authors: Robert W Shafer, Michael J Kozal, Mark A Winters, Astrid K N Iversen, David Katzenstein, Margaret V Ragni, William A Meyer, Phalquni Gupta, Suraiya Rasheed, Robert W. Coombs
    Abstract:

    Drug Resistance conferred by specific human immunodeficiency virus type 1 (HIV-1) pol gene Mutations has been associated with clinical progression in HIV-infected patients receiving anti-retroviral therapy. This study examined drug susceptibilities and pol Mutations of HIV-1 strains from patients treated for 1 year with zidovudine, didanosine (ddI), or zidovudine and ddI. Ten (42%) of 24 patients receiving combination therapy versus 8/26 (31%) receiving only zidovudine had HIV-1 strains with phenotypic zidovudine Resistance or a zidovudine Resistance pol Mutation at codon 215 (P = .6). In contrast, a ddI Resistance Mutation at codon 74 was less common among patients receiving combination therapy (2/24) than among those receiving ddI only (17/26; P < .001). Two patients receiving combination therapy developed Resistance to zidovudine and ddI; they had HIV strains with amino acid Mutations at codons 62, 75, 77, 116, and 151. Combination therapy with zidovudine and ddI selects for zidovudine-resistant HIV-1 strains lacking a ddI Resistance Mutation and for multidrug-resistant strains containing novel pol Mutations.

Astrid K N Iversen - One of the best experts on this subject based on the ideXlab platform.

Robert W. Coombs - One of the best experts on this subject based on the ideXlab platform.

Jonathan Weiss - One of the best experts on this subject based on the ideXlab platform.

  • chemogenomic profiling provides insights into the limited activity of irreversible egfr inhibitors in tumor cells expressing the t790m egfr Resistance Mutation
    Cancer Research, 2010
    Co-Authors: Haridas B Rode, Stefanie Heynck, Martin Peifer, Florian Fischer, Sabine Kluter, Vijaykumar Pawar, Cecile Reuter, Johannes M Heuckmann, Jonathan Weiss, Lars Ruddigkeit
    Abstract:

    Reversible epidermal growth factor receptor (EGFR) inhibitors are the first class of small molecules to improve progression-free survival of patients with EGFR-mutated lung cancers. Second-generation EGFR inhibitors introduced to overcome acquired Resistance by the T790M Resistance Mutation of EGFR have thus far shown limited clinical activity in patients with T790M-mutant tumors. In this study, we systematically analyzed the determinants of the activity and selectivity of the second-generation EGFR inhibitors. A focused library of irreversible as well as structurally corresponding reversible EGFR-inhibitors was synthesized for chemogenomic profiling involving over 79 genetically defined NSCLC and 19 EGFR-dependent cell lines. Overall, our results show that the growth-inhibitory potency of all irreversible inhibitors against the EGFRT790M Resistance Mutation was limited by reduced target inhibition, linked to decreased binding velocity to the mutant kinase. Combined treatment of T790M-mutant tumor cells with BIBW-2992 and the phosphoinositide-3-kinase/mammalian target of rapamycin inhibitor PI-103 led to synergistic induction of apoptosis. Our findings offer a mechanistic explanation for the limited efficacy of irreversible EGFR inhibitors in EGFRT790M gatekeeper-mutant tumors, and they prompt combination treatment strategies involving inhibitors that target signaling downstream of the EGFR. Cancer Res; 70(3); 868–74

  • Chemogenomic Profiling Provides Insights into the Limited Activity of Irreversible EGFR Inhibitors in Tumor Cells Expressing the T790M EGFR Resistance Mutation
    Cancer research, 2010
    Co-Authors: Martin L. Sos, Haridas B Rode, Stefanie Heynck, Martin Peifer, Florian Fischer, Sabine Kluter, Vijaykumar Pawar, Cecile Reuter, Johannes M Heuckmann, Jonathan Weiss
    Abstract:

    Reversible epidermal growth factor receptor (EGFR) inhibitors are the first class of small molecules to improve progression-free survival of patients with EGFR-mutated lung cancers. Second-generation EGFR inhibitors introduced to overcome acquired Resistance by the T790M Resistance Mutation of EGFR have thus far shown limited clinical activity in patients with T790M-mutant tumors. In this study, we systematically analyzed the determinants of the activity and selectivity of the second-generation EGFR inhibitors. A focused library of irreversible as well as structurally corresponding reversible EGFR-inhibitors was synthesized for chemogenomic profiling involving over 79 genetically defined NSCLC and 19 EGFR-dependent cell lines. Overall, our results show that the growth-inhibitory potency of all irreversible inhibitors against the EGFR(T790M) Resistance Mutation was limited by reduced target inhibition, linked to decreased binding velocity to the mutant kinase. Combined treatment of T790M-mutant tumor cells with BIBW-2992 and the phosphoinositide-3-kinase/mammalian target of rapamycin inhibitor PI-103 led to synergistic induction of apoptosis. Our findings offer a mechanistic explanation for the limited efficacy of irreversible EGFR inhibitors in EGFR(T790M) gatekeeper-mutant tumors, and they prompt combination treatment strategies involving inhibitors that target signaling downstream of the EGFR.

  • pten loss contributes to erlotinib Resistance in egfr mutant lung cancer by activation of akt and egfr
    Cancer Research, 2009
    Co-Authors: Martin L. Sos, Stefanie Heynck, Florian Fischer, Jonathan Weiss, Mirjam Koker, Barbara A Weir, Rosalia Rabinovsky, Thomas Zander, Jens M Seeger, Peter Frommolt
    Abstract:

    Clinical Resistance to epidermal growth factor receptor (EGFR) inhibition in lung cancer has been linked to the emergence of the EGFR T790M Resistance Mutation or amplification of MET. Additional mechanisms contributing to EGFR inhibitor Resistance remain elusive. By applying combined analyses of gene expression, copy number, and biochemical analyses of EGFR inhibitor responsiveness, we identified homozygous loss of PTEN to segregate EGFR-dependent and EGFR-independent cells. We show that in EGFR-dependent cells, PTEN loss partially uncouples mutant EGFR from downstream signaling and activates EGFR, thereby contributing to erlotinib Resistance. The clinical relevance of our findings is supported by the observation of PTEN loss in 1 out of 24 primary EGFR-mutant non-small cell lung cancer (NSCLC) tumors. These results suggest a novel Resistance mechanism in EGFR-mutant NSCLC involving PTEN loss.

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