14 results on '"Jean-Marc, Plesséria"'
Search Results
2. Selection of a CXCR4 antagonist from a human heavy chain CDR3-derived phage library
- Author
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Jean-Marc Plesséria, Aurélie Fischer, Julie Mathu, Sabrina Deroo, Andy Chevigné, Nadia Beaupain, Jean-Claude Schmit, and Manuel Counson
- Subjects
chemistry.chemical_classification ,Heavy chain ,CXCR4 antagonist ,Phage display ,Repertoire ,Peptide ,Cell Biology ,Computational biology ,Biology ,Biochemistry ,Molecular biology ,chemistry ,Sequence variation ,Amino acid content ,Receptor ,Molecular Biology - Abstract
Phage display technology is a powerful selection approach to identify strong and specific binders to a large variety of targets. In this study, we compared the efficacy of a phage library displaying human heavy chain complementarity determining region 3 (HCDR3) repertoires with a set of conventional random peptide libraries for the identification of CXCR4 antagonists using a peptide corresponding to the second extracellular loop of the receptor CXCR4 as target. A total of 11 selection campaigns on this target did not result in any specific ligand from the random peptide libraries. In contrast, a single selection campaign with an HCDR3 library derived from the IgM repertoire of a nonimmunized donor resulted in nine specific peptides with lengths ranging from 10 to 19 residues. Four of these HCDR3 sequences interacted with native receptor and the most frequently isolated peptide displayed an affinity of 5.6 μm and acted as a CXCR4 antagonist (IC50 = 23 μm). To comprehend the basis of the highly efficient HCDR3 library selection, its biochemical properties were investigated. The HCDR3 length varied from 3 to 21 residues and displayed a biased amino acid content with a predominant proportion of Tyr, Gly, Ser and Asp. Repetitive and conserved motifs were observed in the majority of the HCDR3 sequences. The strength and efficacy of the HCDR3 libraries reside in the combination of multiple size peptides and a naturally biased sequence variation. Therefore, HCDR3 libraries represent a powerful and versatile alternative to fully randomized peptide libraries, in particular for difficult targets.
- Published
- 2011
- Full Text
- View/download PDF
3. A new recombinant virus system for the study of HIV-1 entry and inhibition
- Author
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Jean-Claude Schmit, Jean-Marc Plesséria, Sabrina Deroo, Claude P. Muller, Wim Ammerlaan, Vic Arendt, François Schneider, François Roman, and Robert Hemmer
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viruses ,virus diseases ,Enfuvirtide ,Biology ,Flow Cytometry ,Virus Replication ,Recombinant virus ,Gp41 ,Virology ,HIV Envelope Protein gp41 ,Peptide Fragments ,Virus ,Restriction enzyme ,Plasmid ,Amino Acid Substitution ,Proviruses ,HIV Fusion Inhibitors ,Valine ,Drug Resistance, Viral ,HIV-1 ,Cloning, Molecular ,Isoleucine ,Gene - Abstract
The construction is described of a HIV-1 proviral, eGFP-tagged plasmid that allows for the recombination of any selected env gene without the use of restriction enzymes and for the quantitation of the infection by the recombinant virus using flow cytometry. The system was tested showing that an isoleucine to valine substitution at residue position 37 of the HIV-1 gp41 impairs the fitness of the virus but does not lead by itself to T-20 resistance.
- Published
- 2006
- Full Text
- View/download PDF
4. O4 Spatial distribution of HIV in antiretroviral-treated humanised mice
- Author
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Coralie Guerin, Linos Vandekerckhove, Jean-Marc Plesséria, Virginie Fievez, Charlène Verschueren, Ward De Spiegelaere, Michel Moutschen, and Carole Devaux
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Epidemiology ,business.industry ,Immunology ,Public Health, Environmental and Occupational Health ,Human immunodeficiency virus (HIV) ,medicine.disease_cause ,Spatial distribution ,Virology ,Microbiology ,QR1-502 ,Infectious Diseases ,medicine ,Public aspects of medicine ,RA1-1270 ,business - Published
- 2016
5. Longitudinal Use of a Line Probe Assay for Human Immunodeficiency Virus Type 1 Protease Predicts Phenotypic Resistance and Clinical Progression in Patients Failing Highly Active Antiretroviral Therapy
- Author
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François Schneider, Thérèse Staub, Elodie Fontaine, Jean-Marc Plesséria, Robert Hemmer, Christine Lambert, Jean Servais, Jean-Claude Schmit, Isabelle Robert, and Vic Arendt
- Subjects
medicine.medical_treatment ,HIV Infections ,Biology ,Antiviral Agents ,Nucleoside Reverse Transcriptase Inhibitor ,HIV Protease ,Predictive Value of Tests ,Indinavir ,Antiretroviral Therapy, Highly Active ,medicine ,Humans ,HIV Protease Inhibitor ,Pharmacology (medical) ,Protease inhibitor (pharmacology) ,Treatment Failure ,Retrospective Studies ,Pharmacology ,Protease ,Drug Resistance, Microbial ,HIV Protease Inhibitors ,Viral Load ,Virology ,Phenotype ,Infectious Diseases ,Nelfinavir ,Mutation ,Disease Progression ,Ritonavir ,Saquinavir ,medicine.drug - Abstract
An observational study assessed the longitudinal use of a new line probe assay for the detection of protease mutations. Probe assays for detection of reverse transcriptase (Inno-LiPA HIV-1 RT; Innogenetics) and protease (prototype kit Inno-LiPA HIV Protease; Innogenetics) mutations gave results for 177 of 199 sequential samples collected over 2 years from 26 patients failing two nucleoside reverse transcriptase inhibitors and one protease inhibitor (first line: indinavir, n = 6; ritonavir, n = 10; and saquinavir, n = 10). Results were compared to recombinant virus protease inhibitor susceptibility data ( n = 87) and to clinical and virological data. Combinations of protease mutations (M46I, G48V, I54V, V82A or -F, I84V, and L90M) predicted phenotypic resistance to the protease inhibitor and to nelfinavir. The sum of protease mutations was associated with virological and clinical outcomes from 6 and 3 months on, respectively. Moreover, a poorer clinical outcome was linked to the sum of reverse transcriptase mutations. In conclusion, despite the limited number of patients studied and the restricted number of codons investigated, probe assay-based genotyping correlates with phenotypic drug resistance and predicts new Centers for Disease Control and Prevention stage B and C clinical events and virological outcome. Line probe assays provide additional prognostic information and should be prospectively investigated for their potential for treatment monitoring.
- Published
- 2002
- Full Text
- View/download PDF
6. Multimeric FHR4 immunoconjugates promote efficient activation of CAP on Her2 tumour cells, further controlled by overexpressed mCRPs, limiting MAC formation and CDC
- Author
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Jean-Marc Plesséria, Charlène Verschueren, Carole Devaux, Xavier Dervillez, Jacques Cohen, and Gilles Iserentant
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Biochemistry ,Chemistry ,Immunology ,Limiting ,Molecular Biology ,MAC formation ,Cell biology - Published
- 2017
- Full Text
- View/download PDF
7. Variant Human Immunodeficiency Virus Type 1 Proteases and Response to Combination Therapy Including a Protease Inhibitor
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Elodie Fontaine, Vic Arendt, Robert Hemmer, Jean Servais, Jean-Marc Plesséria, Isabelle Robert, Guy Burtonboy, Christine Lambert, Jean-Claude Schmit, François Schneider, and Thérèse Staub
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Adult ,Male ,Proteases ,medicine.medical_treatment ,HIV Infections ,Antiviral Agents ,Virus ,HIV Protease ,Indinavir ,medicine ,Humans ,HIV Protease Inhibitor ,Pharmacology (medical) ,Longitudinal Studies ,Pharmacology ,Polymorphism, Genetic ,Protease ,biology ,Genetic Variation ,HIV Protease Inhibitors ,biology.organism_classification ,Virology ,Infectious Diseases ,Multivariate Analysis ,Lentivirus ,HIV-1 ,Drug Therapy, Combination ,Female ,Ritonavir ,Saquinavir ,medicine.drug - Abstract
The objective of this observational study was to assess the genetic variability in the human immunodeficiency virus (HIV) protease gene from HIV type 1 (HIV-1)-positive (clade B), protease inhibitor-naı̈ve patients and to evaluate its association with the subsequent effectiveness of a protease inhibitor-containing triple-drug regimen. The protease gene was sequenced from plasma-derived virus from 116 protease inhibitor-naı̈ve patients. The virological response to a triple-drug regimen containing indinavir, ritonavir, or saquinavir was evaluated every 3 months for as long as 2 years ( n = 40). A total of 36 different amino acid substitutions compared to the reference sequence (HIV-1 HXB2) were detected. No substitutions at the active site similar to the primary resistance mutations were found. The most frequent substitutions (prevalence, >10%) at baseline were located at codons 15, 13, 12, 62, 36, 64, 41, 35, 3, 93, 77, 63, and 37 (in ascending order of frequency). The mean number of polymorphisms was 4.2. A relatively poorer response to therapy was associated with a high number of baseline polymorphisms and, to a lesser extent, with the presence of I93L at baseline in comparison with the wild-type virus. A71V/T was slightly associated with a poorer response to first-line ritonavir-based therapy. In summary, within clade B viruses, protease gene natural polymorphisms are common. There is evidence suggesting that treatment response is associated with this genetic background, but most of the specific contributors could not be firmly identified. I93L, occurring in about 30% of untreated patients, may play a role, as A71V/T possibly does in ritonavir-treated patients.
- Published
- 2001
- Full Text
- View/download PDF
8. Neutralising properties of peptides derived from CXCR4 extracellular loops towards CXCL12 binding and HIV-1 infection
- Author
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Virginie Fievez, Andy Chevigné, Martyna Szpakowska, Aurélie Fischer, Jean-Marc Plesséria, Sabrina Deroo, Jean-Claude Schmit, and Manuel Counson
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Chemokine ,Receptors, CXCR4 ,Chemokine receptor CCR5 ,Molecular Sequence Data ,HIV Infections ,C-C chemokine receptor type 6 ,Extracellular loops ,Chemokine receptor ,GPCR ,Viral entry ,Neutralization Tests ,Humans ,Amino Acid Sequence ,Receptor ,Molecular Biology ,Peptide sequence ,G protein-coupled receptor ,CXCR4 ,biology ,Cell Biology ,CXCL12 ,Molecular biology ,CXCR7 ,Chemokine CXCL12 ,Cell biology ,biology.protein ,HIV-1 ,Peptides - Abstract
The chemokine receptor CXCR4 interacts with a single endogenous chemokine, CXCL12, and regulates a wide variety of physiological and pathological processes including inflammation and metastasis development. CXCR4 also binds the HIV-1 envelope glycoprotein, gp120, resulting in viral entry into host cells. Therefore, CXCR4 and its ligands represent valuable drug targets. In this study, we investigated the inhibitory properties of synthetic peptides derived from CXCR4 extracellular loops (ECL1-X4, ECL2-X4 and ECL3-X4) towards HIV-1 infection and CXCL12-mediated receptor activation. Among these peptides, ECL1-X4 displayed anti-HIV-1 activity against X4, R5/X4 and R5 viruses (IC50=24 to 76μM) in cell viability assay without impairing physiological CXCR4–CXCL12 signalling. In contrast, ECL2-X4 only inhibited X4 and R5/X4 strains, interfering with HIV-entry into cells. At the same time, ECL2-X4 strongly and specifically interacted with CXCL12, blocking its binding to CXCR4 and its second receptor, CXCR7 (IC50=20 and 100μM). Further analysis using mutated and truncated peptides showed that ECL2 of CXCR4 forms multiple contacts with the gp120 protein and the N-terminus of CXCL12. Chemokine neutralisation was mainly driven by four aspartates and the C-terminal residues of ECL2-X4. These results demonstrate that ECL2 represents an important structural determinant in CXCR4 activation. We identified the putative site for the binding of CXCL12 N-terminus and provided new structural elements to explain the recognition of gp120 and dimeric CXCR4 ligands.
- Published
- 2013
9. Selection of a CXCR4 antagonist from a human heavy chain CDR3-derived phage library
- Author
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Andy, Chevigné, Aurélie, Fischer, Julie, Mathu, Manuel, Counson, Nadia, Beaupain, Jean-Marc, Plesséria, Jean-Claude, Schmit, and Sabrina, Deroo
- Subjects
Receptors, CXCR4 ,Immunoglobulin M ,Peptide Library ,Humans ,Amino Acid Sequence ,Complementarity Determining Regions ,Gene Library - Abstract
Phage display technology is a powerful selection approach to identify strong and specific binders to a large variety of targets. In this study, we compared the efficacy of a phage library displaying human heavy chain complementarity determining region 3 (HCDR3) repertoires with a set of conventional random peptide libraries for the identification of CXCR4 antagonists using a peptide corresponding to the second extracellular loop of the receptor CXCR4 as target. A total of 11 selection campaigns on this target did not result in any specific ligand from the random peptide libraries. In contrast, a single selection campaign with an HCDR3 library derived from the IgM repertoire of a nonimmunized donor resulted in nine specific peptides with lengths ranging from 10 to 19 residues. Four of these HCDR3 sequences interacted with native receptor and the most frequently isolated peptide displayed an affinity of 5.6 μm and acted as a CXCR4 antagonist (IC(50) = 23 μm). To comprehend the basis of the highly efficient HCDR3 library selection, its biochemical properties were investigated. The HCDR3 length varied from 3 to 21 residues and displayed a biased amino acid content with a predominant proportion of Tyr, Gly, Ser and Asp. Repetitive and conserved motifs were observed in the majority of the HCDR3 sequences. The strength and efficacy of the HCDR3 libraries reside in the combination of multiple size peptides and a naturally biased sequence variation. Therefore, HCDR3 libraries represent a powerful and versatile alternative to fully randomized peptide libraries, in particular for difficult targets.
- Published
- 2011
10. HIV-1 subtypes in Luxembourg, 1983-2000
- Author
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Sabrina Deroo, Robert Hemmer, Thérèse Staub, Jean-Claude Schmit, Elodie Fontaine, François Schneider, Vic Arendt, Christine Lambert, Isabelle Robert, and Jean-Marc Plesséria
- Subjects
Adult ,Male ,Genotype ,Luxembourg ,medicine.medical_treatment ,Immunology ,HIV Infections ,Biology ,Virus ,HIV Protease ,Antiretroviral Therapy, Highly Active ,Drug Resistance, Viral ,medicine ,Prevalence ,Immunology and Allergy ,HIV Protease Inhibitor ,Humans ,Genotyping ,Aged ,Retrospective Studies ,Protease ,Polymorphism, Genetic ,HIV Protease Inhibitors ,Middle Aged ,biology.organism_classification ,Virology ,Reverse transcriptase ,HIV Reverse Transcriptase ,Infectious Diseases ,Lentivirus ,Mutation ,HIV-1 ,Reverse Transcriptase Inhibitors ,Female ,Viral disease ,HIV drug resistance - Abstract
Objectives: To study the prevalence of HIV-1 subtypes in Luxembourg between 1983 and 2000. To compare the drug susceptibility of non-B and B clade viruses and the prevalence of resistance-associated mutations and polymorphisms before antiretroviral treatment. Design: A retrospective study on plasma samples of HIV-infected patients registered at the National Service of Infectious Diseases, Luxembourg, between 1983 and 2000. Methods: Genotyping was performed by sequencing of the reverse transcriptase (RT) and protease coding region of the pol gene. Drug susceptibility was assessed in a recombinant virus assay. Results: A total of 20.1% of the HIV-positive patients were infected with non-B subtypes, and since 1990 the proportion of non-B viruses has increased ninefold. Eleven out of 14 F1 subtypes occurred in patients native to Luxembourg. Major resistance mutations related to protease inhibitors (PI), nucleoside reverse transcriptase inhibitors (NRTI) and non-nucleoside reverse transcriptase inhibitors (NNRTI) occurred in less than 3% of treatment-naive viruses; however, 87% of the viruses had at least one PI-associated mutation. Natural polymorphism of the protease and RT coding region was observed more frequently among non-B than B viruses. Significantly more B viruses displayed resistance to the tested PI, NRTI and NNRTI (P= 0.044). Conclusion: The proportion of non-B viruses has increased dramatically since 1990. Non-B subtypes showed no decreased susceptibility to antiretroviral drugs, but displayed minor mutations and polymorphisms at higher frequency in their protease and RT coding region. In contrast, a significantly higher proportion of B viruses showed resistance to a range of antiretroviral drugs.
- Published
- 2002
11. Longitudinal use of phenotypic resistance testing to HIV-1 protease inhibitors in patients developing HAART failure
- Author
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Jean, Servais, Jean-Marc, Plesséria, Christine, Lambert, Elodie, Fontaine, Isabelle, Robert, Vic, Arendt, Thérèse, Staub, François, Schneider, Robert, Hemmer, and Jean-Claude, Schmit
- Subjects
Phenotype ,Predictive Value of Tests ,Antiretroviral Therapy, Highly Active ,Drug Resistance, Viral ,HIV-1 ,Humans ,HIV Infections ,HIV Protease Inhibitors ,Longitudinal Studies ,Microbial Sensitivity Tests ,Treatment Failure - Abstract
An "in-house" recombinant virus protease inhibitor susceptibility assay was carried out (median of 3 per patient) retrospectively in 26 patients failing HIV protease inhibitor based therapy at regular intervals to the initiation of the first protease inhibitor. Patients were treated with either indinavir (N = 6), ritonavir (N = 10), or saquinavir (N = 10) and two nucleoside analogues. Second line therapy was based on single or dual protease inhibitor regimens occasionally containing nelfinavir. Clinically relevant resistance cut-offs associated with a poorer virological outcome from 6 months on and the clinical outcome from 3 months on were determined tentatively as 4- to 8-fold resistance for indinavir and ritonavir and 2.5- to 8-fold to saquinavir. In addition, the degree of cross-resistance at the time of the change of protease inhibitor was associated with the response in viral load at 6 months to the second line therapy (P = 0.018). Cross-resistance (or = 8-fold) between ritonavir and indinavir was common (78 and 100%). Cross-resistance between indinavir or ritonavir and saquinavir was less frequent (75 and 60% respectively) than the opposite (100%, P = 0.004). Cross-resistance to nelfinavir was encountered more frequently (70%) than to amprenavir (9%). The magnitudes of resistance were correlated between each other. In summary, the protease inhibitor susceptibility carried out longitudinally appears to be an earlier prognostic marker than viral load in a context of cross-resistance. The magnitude of resistance, as a marker of cross-resistance, should be useful to guide second line therapy.
- Published
- 2002
12. Genotypic correlates of resistance to HIV-1 protease inhibitors on longitudinal data: the role of secondary mutations
- Author
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Christine Lambert, Isabelle Robert, Elodie Fontaine, Jean-Marc Plesséria, Jean Servais, Thérèse Staub, François Schneider, Jean-Claude Schmit, Robert Hemmer, and Vic Arendt
- Subjects
Adult ,Male ,Longitudinal study ,Genotype ,medicine.disease_cause ,Virus ,HIV-1 protease ,HIV Protease ,Drug Resistance, Viral ,medicine ,Humans ,Pharmacology (medical) ,Protease inhibitor (pharmacology) ,Longitudinal Studies ,Pharmacology ,Genetics ,Mutation ,Acquired Immunodeficiency Syndrome ,biology ,HIV Protease Inhibitors ,Middle Aged ,Viral Load ,biology.organism_classification ,Virology ,CD4 Lymphocyte Count ,Infectious Diseases ,Cross-Sectional Studies ,Enzyme inhibitor ,Lentivirus ,biology.protein ,Female - Abstract
Direct sequencing of the pol gene was assessed retrospectively with protease inhibitor susceptibility in a longitudinal study. A total of 134 samples from 26 patients were analysed at regular intervals up to 2 years. Patients were included in virological failure despite indinavir, ritonavir or saquinavir based triple-drug therapy. Both the type and number of certain secondary protease mutations modulated the effect of primary mutations on phenotypic resistance. This was notably applicable to L10I/V, and to lesser extents to A71V/T. However, combinations of primary mutations, including I54V could predict resistance to the drug used and nelfinavir in more than 80%. In contrast, in vitro cross-resistance to amprenavir was rarely encountered. In addition, there was a relationship between a higher number of key mutations and poorer virological and clinical outcomes, respectively, from 6 and 3 months on. The key mutations were the protease mutations independently conferring phenotypic resistance and/or the reverse transcriptase mutations predicting treatment outcome. This relationship was independent from drug history, viral load and CD4 cell count measurements. In summary, even on a small sample size, sequence-based genotyping seems to be a good prognostic marker when performed longitudinally. In the context of primary resistance mutations, including additional secondary mutations, it may be useful in the prediction of phenotypic and clinical resistance. This should be assessed to optimize treatment monitoring before emergence of broadly cross-resistant virus.
- Published
- 2002
13. Comparison of DNA sequencing and a line probe assay for detection of human immunodeficiency virus type 1 drug resistance mutations in patients failing highly active antiretroviral therapy
- Author
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Thérèse Staub, Robert Hemmer, Jean-Marc Plesséria, Jean Servais, François Schneider, Jean-Claude Schmit, Guy Burtonboy, Isabelle Robert, Vic Arendt, Elodie Fontaine, and Christine Lambert
- Subjects
Microbiology (medical) ,Adult ,Male ,Genotype ,HIV Infections ,Indinavir ,Drug resistance ,Biology ,Polymerase Chain Reaction ,Virus ,HIV Protease ,Antiretroviral Therapy, Highly Active ,Virology ,medicine ,HIV Protease Inhibitor ,Humans ,Protease inhibitor (pharmacology) ,Treatment Failure ,Saquinavir ,Retrospective Studies ,Acquired Immunodeficiency Syndrome ,Ritonavir ,Drug Resistance, Microbial ,HIV Protease Inhibitors ,Reverse transcriptase ,HIV Reverse Transcriptase ,Mutation ,HIV-1 ,RNA, Viral ,Female ,medicine.drug - Abstract
The resistance of human immunodeficiency virus type 1 (HIV-1) to drugs is a major cause of antiretroviral treatment failure. We have compared direct sequencing to a line probe assay (LiPA) for the detection of drug resistance-related mutations in 197 clinical samples, and we have investigated the sequential appearance of mutations under drug pressure. For 26 patients with virological failure despite the use of two nucleoside analogues and one protease inhibitor (indinavir [ n = 6], ritonavir [ n = 10], and saquinavir [ n = 10]), genotypic resistance assays were carried out retrospectively every 3 months for up to 2 years by using direct sequencing (TruGene; Visible Genetics) and a LiPA for detection of mutations in the reverse transcriptase (INNO-LiPA HIV-1 RT; Innogenetics) and the protease (INNO-LiPA HIV Protease, prototype version; Innogenetics) genes. Comparison of the results from both assays found rare major discrepancies (
- Published
- 2001
14. Impact on replicative fitness of the G48E substitution in the protease of HIV-1 - An in vitro and in silico evaluation
- Author
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Jean-Marc Plesséria, Jean-Marie Zimmer, Abel Jonckheer, Kristel Van Laethem, Miguel E. Quiñones-Mateu, Marc De Maeyer, François Roman, Kris Covens, Jean-Claude Schmit, Anne-Mieke Vandamme, Jan Weber, Christine Lambert, Jean-Yves Servais, and Ana C. Vazquez
- Subjects
medicine.medical_treatment ,Mutant ,Drug Resistance ,Reversion ,HIV Infections ,Context (language use) ,In Vitro Techniques ,Biology ,Virus Replication ,medicine.disease_cause ,Virus ,HIV Protease ,medicine ,Humans ,Protease Inhibitors ,Pharmacology (medical) ,Saquinavir ,Genetics ,Mutation ,Polymorphism, Genetic ,Protease ,Wild type ,Virology ,Infectious Diseases ,Viral replication ,HIV-1 - Abstract
Summary: We observed an unusual glycine-to-glutamate substitution at protease (PR) residue position 48 (G48E) in an African patient infected with a subtype A1 HIV-1 strain failing a saquinavir-containing regimen. Phenotypic analysis of protease inhibitor (PI) susceptibility showed that the G48E site-directed mutant, when introduced into an NL4-3 HIV-1 PR backbone, was slightly resistant to SQV (2-fold when compared with the wild-type virus). In addition, the G48E and G48E/V82A site-directed mutants were associated with a decrease in fitness, whereas a reversion to the wild type at position 48 was observed in vitro. Growth competition experiments using a novel growth competition assay based on enhanced green fluorescent protein- or Discosoma spp. red fluorescent protein-expressing viruses showed that the replicative fitness of the G48E virus was reduced to 55% compared with the parental NL4-3 virus. Synthesizing all possible site-directed mutants found in the patient strain is too time-consuming; therefore, a molecular dynamics (MD) simulation approach was used to understand why this mutation survived despite its fitness cost. These simulations documented that the G48E mutant interacted with PI resistance mutations (M46I, I54V, Q58E, and L63P) and with natural polymorphisms specific to subtype A1 (E35D, M36I, and R57K) that were present in the patient's virus. We hypothesize that the polymorphisms contained in the PR flap regions of the patient's virus may compensate for the presence of G48E, possibly by restoring the flexibility of the PR flaps. In summary, our results demonstrate that the G48E substitution, when introduced in the context of an HIV-1 subtype B strain, is highly unstable and gives rise to viruses with a poor replicative fitness in vitro. We also showed that when confronted with too many mutations to evaluate in vitro, MD simulations are helpful to draft hypotheses on how polymorphisms can interact with resistance mutations to stabilize their potential fitness cost.
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