scholarly journals A Novel Genetic Pathway of Human Immunodeficiency Virus Type 1 Resistance to Stavudine Mediated by the K65R Mutation

2003 ◽  
Vol 77 (10) ◽  
pp. 5685-5693 ◽  
Author(s):  
J. Gerardo García-Lerma ◽  
Hamish MacInnes ◽  
Diane Bennett ◽  
Patrick Reid ◽  
Soumya Nidtha ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Phenotypic Expression ◽  
Cross Resistance ◽  
Phenotypic Characterization ◽  
Immunodeficiency Virus ◽  
Hiv 1 ◽  
Selection Of

ABSTRACT Stavudine (d4T) and zidovudine (AZT) are thymidine analogs widely used in the treatment of human immunodeficiency virus type 1 (HIV-1)-infected persons. Resistance to d4T is not fully understood, although the selection of AZT resistance mutations in patients treated with d4T suggests that both drugs have similar pathways of resistance. Through the analysis of genotypic changes in nine recombinant viruses cultured with d4T, we identified a new pathway for d4T resistance mediated by K65R, a mutation not selected by AZT. Passaged viruses were derived from treatment-naïve persons or HIV-1HXB2 and had wild-type reverse transcriptase (RT) or T215C/D mutations. K65R was selected in seven viruses and was associated with a high level of enzymatic resistance to d4T-triphosphate (median, 16-fold; range, 5- to 48-fold). The role of K65R in d4T resistance was confirmed in site-directed mutants generated in three different RT backgrounds. Phenotypic assays based on recombinant single-cycle replication or a whole-virus multiple replication cycle were unable to detect d4T resistance in d4T-selected mutants with K65R but detected cross-resistance to other nucleoside RT inhibitors. Four of the six viruses that had 215C/D mutations at baseline acquired the 215Y mutation alone or in association with K65R. Mutants having K65R and T215Y replicated less efficiently than viruses that had T215Y only, suggesting that selection of T215Y in patients treated with d4T may be favored. Our results demonstrate that K65R plays a role in d4T resistance and indicate that resistance pathways for d4T and AZT may not be identical. Biochemical analysis and improved replication assays are both required for a full phenotypic characterization of resistance to d4T. These findings highlight the complexity of the genetic pathways of d4T resistance and its phenotypic expression.

scholarly journals A Mutation in Human Immunodeficiency Virus Type 1 Protease, N88S, That Causes In Vitro Hypersensitivity to Amprenavir

2000 ◽  
Vol 74 (9) ◽  
pp. 4414-4419 ◽  
Author(s):  
Rainer Ziermann ◽  
Kay Limoli ◽  
Kalyan Das ◽  
Edward Arnold ◽  
Christos J. Petropoulos ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Salvage Therapy ◽  
The United States ◽  
Site Directed Mutagenesis ◽  
Cross Resistance ◽  
Immunodeficiency Virus ◽  
Hiv 1

ABSTRACT Amprenavir (Agenerase, 141-W94, VX-478) is a human immunodeficiency virus type 1 (HIV-1) protease inhibitor (PRI) recently approved for the treatment of HIV-1 infection in the United States. A major cause of treatment failure is the development of resistance to PRIs. One potential use for amprenavir is as salvage therapy for patients for whom treatment that includes one (or more) of the other four currently approved PRIs—saquinavir, indinavir, ritonavir, and nelfinavir—has failed. We evaluated the cross-resistance to amprenavir of viruses that evolved during treatment with the two most commonly prescribed PRIs, nelfinavir and indinavir. Unexpectedly, a dramatic increase in susceptibility (2.5- to 12.5-fold) was observed with 20 of 312 (6.4%) patient viruses analyzed. The most pronounced increases in susceptibility were strongly associated with an N88S mutation in protease. All viruses that carried the N88S mutation were hypersensitive to amprenavir. Site-directed mutagenesis studies confirmed the causal role of N88S in determining amprenavir hypersensitivity. The presence of the N88S mutation and associated amprenavir hypersensitivity may be useful in predicting an improved clinical response to amprenavir salvage therapy.

scholarly journals TMC310911, a Novel Human Immunodeficiency Virus Type 1 Protease Inhibitor, ShowsIn Vitroan Improved Resistance Profile and Higher Genetic Barrier to Resistance Compared with Current Protease Inhibitors

2011 ◽  
Vol 55 (12) ◽  
pp. 5723-5731 ◽  
Author(s):  
Inge Dierynck ◽  
Herwig Van Marck ◽  
Marcia Van Ginderen ◽  
Tim H. M. Jonckers ◽  
Madhavi N. L. Nalam ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Protease Inhibitor ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Clinical Isolates ◽  
Immunodeficiency Virus ◽  
Hiv 1 ◽  
Selection Of

ABSTRACTTMC310911 is a novel human immunodeficiency virus type 1 (HIV-1) protease inhibitor (PI) structurally closely related to darunavir (DRV) but with improved virological characteristics. TMC310911 has potent activity against wild-type (WT) HIV-1 (median 50% effective concentration [EC50], 14 nM) and a wide spectrum of recombinant HIV-1 clinical isolates, including multiple-PI-resistant strains with decreased susceptibility to currently approved PIs (fold change [FC] in EC50, >10). For a panel of 2,011 recombinant clinical isolates with decreased susceptibility to at least one of the currently approved PIs, the FC in TMC310911 EC50was ≤4 for 82% of isolates and ≤10 for 96% of isolates. The FC in TMC310911 EC50was ≤4 and ≤10 for 72% and 94% of isolates with decreased susceptibility to DRV, respectively.In vitroresistance selection (IVRS) experiments with WT virus and TMC310911 selected for mutations R41G or R41E, but selection of resistant virus required a longer time than IVRS performed with WT virus and DRV. IVRS performed with r13025, a multiple-PI-resistant recombinant clinical isolate, and TMC310911 selected for mutations L10F, I47V, and L90M (FC in TMC310911 EC50= 16). IVRS performed with r13025 in the presence of DRV required less time and resulted in more PI resistance-associated mutations (V32I, I50V, G73S, L76V, and V82I; FC in DRV EC50= 258). The activity against a comprehensive panel of PI-resistant mutants and the limitedin vitroselection of resistant viruses under drug pressure suggest that TMC310911 represents a potential drug candidate for the management of HIV-1 infection for a broad range of patients, including those with multiple PI resistance.

scholarly journals A Novel Nonnucleoside Analogue That Inhibits Human Immunodeficiency Virus Type 1 Isolates Resistant to Current Nonnucleoside Reverse Transcriptase Inhibitors

2006 ◽  
Vol 51 (2) ◽  
pp. 429-437 ◽  
Author(s):  
Zhijun Zhang ◽  
Wen Xu ◽  
Yung-Hyo Koh ◽  
Jae Hoon Shim ◽  
Jean-Luc Girardet ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Reverse Transcriptase ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Plasma Concentrations ◽  
Cross Resistance ◽  
Double Mutation ◽  
Immunodeficiency Virus ◽  
Hiv 1

ABSTRACT Nonnucleoside reverse transcriptase (RT) inhibitors (NNRTIs) are important components of current combination therapies for human immunodeficiency virus type 1 (HIV-1) infection. However, their low genetic barriers against resistance development, cross-resistance, and serious side effects can compromise the benefits of the two current drugs in this class (efavirenz and nevirapine). In this study, we report a novel and potent NNRTI, VRX-480773, that inhibits viruses from efavirenz-resistant molecular clones and most NNRTI-resistant clinical HIV-1 isolates tested. In vitro mutation selection experiments revealed that longer times were required for viruses to develop resistance to VRX-480773 than to efavirenz. RT mutations selected by VRX-480773 after 3 months of cell culture in the presence of 1 nM VRX-480773 carried the Y181C mutation, resulting in a less-than-twofold increase in resistance to the compound. A virus containing the double mutation V106I-Y181C emerged after 4 months, causing a sixfold increase in resistance. Viruses containing additional mutations of D123G, F227L, and T369I emerged when the cultures were incubated with increasing concentrations of VRX-480773. Most of the resistant viruses selected by VRX-480773 are susceptible to efavirenz. Oral administration of VRX-480773 to dogs resulted in plasma concentrations that were significantly higher than those required for the inhibition of wild-type and mutant viruses. These results warrant further clinical development of VRX-480773 for the treatment of HIV infection in both NNRTI-naive and -experienced patients.

scholarly journals Isolation and Characterization of Human Immunodeficiency Virus Type 1 Resistant to the Small-Molecule CCR5 Antagonist TAK-652

2006 ◽  
Vol 51 (2) ◽  
pp. 707-715 ◽  
Author(s):  
Masanori Baba ◽  
Hiroshi Miyake ◽  
Xin Wang ◽  
Mika Okamoto ◽  
Katsunori Takashima
Keyword(s):  
Human Immunodeficiency Virus ◽  
Amino Acid ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Small Molecule ◽  
Cross Resistance ◽  
Isolation And Characterization ◽  
Immunodeficiency Virus ◽  
Hiv 1

ABSTRACT TAK-652, a novel small-molecule chemokine receptor antagonist, is a highly potent and selective inhibitor of CCR5-using (R5) human immunodeficiency virus type 1 (HIV-1) replication in vitro. Since TAK-652 is orally bioavailable and has favorable pharmacokinetic profiles in humans, it is considered a promising candidate for an entry inhibitor of HIV-1. To investigate the resistance to TAK-652, peripheral blood mononuclear cells were infected with the R5 HIV-1 primary isolate KK and passaged in the presence of escalating concentrations of the compound for more than 1 year. After 67 weeks of cultivation, the escape virus emerged even in the presence of a high concentration of TAK-652. This virus displayed more than 200,000-fold resistance to TAK-652 compared with the wild type. The escape virus appeared to have cross-resistance to the structurally related compound TAK-779 but retained full susceptibility to TAK-220, which is from a different class of CCR5 antagonists. Furthermore, the escape virus was unable to use CXCR4 as a coreceptor. Analysis for Env amino acid sequences of escape viruses at certain points of passage revealed that amino acid changes accumulated with an increasing number of passages. Several amino acid changes not only in the V3 region but also in other Env regions seemed to be required for R5 HIV-1 to acquire complete resistance to TAK-652.

scholarly journals Selection of T1249-Resistant Human Immunodeficiency Virus Type 1 Variants

2008 ◽  
Vol 82 (13) ◽  
pp. 6678-6688 ◽  
Author(s):  
Dirk Eggink ◽  
Christopher E. Baldwin ◽  
Yiqun Deng ◽  
Johannes P. M. Langedijk ◽  
Min Lu ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Cross Resistance ◽  
Fusion Inhibitor ◽  
Third Generation ◽  
The Third ◽  
Immunodeficiency Virus ◽  
Hiv 1

ABSTRACT Human immunodeficiency virus type 1 (HIV-1) entry is an attractive target for therapeutic intervention. Two drugs that inhibit this process have been approved: the fusion inhibitor T20 (enfuvirtide [Fuzeon]) and, more recently, the CCR5 blocker maraviroc (Selzentry). T1249 is a second-generation fusion inhibitor with improved antiviral potency compared to the first-generation peptide T20. We selected T1249-resistant HIV-1 variants in vitro by serial virus passage in the presence of increasing T1249 doses after passage with wild-type and T20-resistant variants. Sequence analysis revealed the acquisition of substitutions within the HR1 region of the gp41 ectodomain. The virus acquired mutations of residue V38 to either E or R in 10 of 19 cultures. Both E and R at position 38 were confirmed to cause resistance to T1249, as well as cross-resistance to T20 and C34, but not to the third-generation fusion inhibitor T2635. We also observed substitutions at residues 79 and 90 (Q79E and K90E), which provide modest resistance to T1249 and, interestingly, T2635. Thus, the gp41 amino acid position implicated in T20 resistance (V38 replaced by A, G, or W) is also responsible for T1249 resistance (V38 replaced by E, R, or K). These results indicate that T20 and T1249 exhibit very similar inhibition modes that call for similar but not identical resistance mutations. All T1249-resistant viruses with changes at position 38 are cross resistant to T20, but not vice versa. Furthermore, substitutions at position 38 do not provide resistance to the third-generation inhibitor T2635, while substitution at positions 79 and 90 do, suggesting different resistance mechanisms.

scholarly journals Isolation and Characterization of Human Immunodeficiency Virus Type-1 Mutants Resistant to the Non-Nucleotide Reverse Transcriptase Inhibitor MKC-442

1995 ◽  
Vol 6 (2) ◽  
pp. 73-79 ◽  
Author(s):  
M. Seki ◽  
Y. Sadakata ◽  
S. Yuasa ◽  
M. Baba
Keyword(s):  
Human Immunodeficiency Virus ◽  
Reverse Transcriptase ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Cross Resistance ◽  
Isolation And Characterization ◽  
Immunodeficiency Virus ◽  
Hiv 1

MKC-442, 6-benzy 1-1-ethoxymethyl-5-isopropyIuraciI (l-EBU), is a potent and selective non-nucleoside inhibitor of human immunodeficiency virus type-1 (HIV-1) reverse transcriptase (RT). Nevirapine, another non-nucleoside RT inhibitor (NNRTI), is associated with rapid emergence of drug-resistant variants during in vitro passages of HIV-1. The emergence of resistant viruses to MKC-442 or nevirapine was examined in vitro. MT-4 cells infected with a clinical isolate (HE) of HIV-1 were cultivated in medium containing excess concentrations of these drugs, and the drug susceptibilities of the breakthrough viruses recovered from the medium were measured. Although nevirapine lost its antiviral activity after six passages, a delay in the emergence of fully resistant viruses was observed for MKC-442. Two resistant clones for each drug were isolated and nucleotide sequences within the RT region were analysed. An amino acid substitution at position 181 (Tyr to Cys) was found, with additional substitutions at positions 103 (Lys to Arg) and 108 (Val to lle) in the MKC-442-resistant viruses. These clones showed various susceptibilities to MKC-442, and cross-resistance to other NNRTIs but not to AZT. These results suggest that the major binding site of MKC-442 on the HIV-1 RT is the tyrosine residue common to these NNRTIs, and that drug resistance to NNRTIs is dependent on both the quality and the quantity of mutations within the HIV-1 RT gene.

scholarly journals Dimer Initiation Signal of Human Immunodeficiency Virus Type 1: Its Role in Partner Selection during RNA Copackaging and Its Effects on Recombination

2007 ◽  
Vol 81 (8) ◽  
pp. 4002-4011 ◽  
Author(s):  
Michael D. Moore ◽  
William Fu ◽  
Olga Nikolaitchik ◽  
Jianbo Chen ◽  
Roger G. Ptak ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Partner Selection ◽  
Base Pairing ◽  
Immunodeficiency Virus ◽  
Virion Formation ◽  
Hiv 1 ◽  
Selection Of

ABSTRACT Frequent human immunodeficiency virus type 1 (HIV-1) recombination occurs during DNA synthesis when portions of the two copackaged RNAs are used as templates to generate a hybrid DNA copy. Therefore, the frequency of copackaging of genomic RNAs from two different viruses (heterozygous virion formation) affects the generation of genotypically different recombinants. We hypothesized that the selection of copackaged RNA partners is largely determined by Watson-Crick pairing at the dimer initiation signal (DIS), a 6-nucleotide palindromic sequence at the terminal loop of stem-loop 1 (SL1). To test our hypothesis, we examined whether heterozygous virion formation could be encouraged by manipulation of the DIS. Three pairs of viruses were generated with compensatory DIS mutations, designed so that perfect DIS base pairing could only occur between RNAs derived from different viruses, not between RNAs from the same virus. We observed that vector pairs with compensatory DIS mutations had an almost twofold increase in recombination rates compared with wild-type viruses. These data suggest that heterozygous virion formation was enhanced in viruses with compensatory DIS mutations (from 50% to more than 90% in some viral pairings). The role of the SL1 stem in heterozygous virion formation was also tested; our results indicated that the intermolecular base pairing of the stem sequences does not affect RNA partner selection. In summary, our results demonstrate that the Watson-Crick pairing of the DIS is a major determinant in the selection of the copackaged RNA partner, and altering the base pairing of the DIS can change the proportion of heterozygous viruses in a viral population. These results also strongly support the hypothesis that HIV-1 RNA dimers are formed prior to encapsidation.

scholarly journals Prevalence and Characteristics of Multinucleoside-Resistant Human Immunodeficiency Virus Type 1 among European Patients Receiving Combinations of Nucleoside Analogues

2000 ◽  
Vol 44 (8) ◽  
pp. 2109-2117 ◽  
Author(s):  
Kristien Van Vaerenbergh ◽  
Kristel Van Laethem ◽  
Jan Albert ◽  
Charles A. B. Boucher ◽  
Bonaventura Clotet ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Response To Treatment ◽  
Cross Resistance ◽  
Resistance Pattern ◽  
Immunodeficiency Virus ◽  
Hiv 1 ◽  
Control Samples

ABSTRACT The prevalence and the genotypic and phenotypic characteristics of multinucleoside-resistant (MNR) human immunodeficiency virus type 1 (HIV-1) variants in Europe were investigated in a multicenter study that involved centers in nine European countries. Study samples (n = 363) collected between 1991 and 1997 from patients exposed to two or more nucleoside analogue reverse transcriptase inhibitors (NRTIs) and 274 control samples from patients exposed to no or one NRTI were screened for two marker mutations of multinucleoside resistance (the Q151M mutation and a mutation with a 2-amino-acid insertion at codon 69, T69S-XX). Q151M was identified in six of the study samples (1.6%), and T69S-XX was identified in two of the study samples (0.5%; both of them T69S-SS), but both patterns were absent among control samples. Non-NRTI (NNRTI)-related changes were observed in viral strains from two patients, which displayed the Q151M resistance pattern, although the patients were NNRTI naive. The patients whose isolates displayed multinucleoside resistance had received treatment with zidovudine and either didanosine, zalcitabine, or stavudine. Both resistance patterns conferred broad cross-resistance to NRTIs in vitro and a poor response to treatment in vivo. MNR HIV-1 is found only among multinucleoside-experienced patients. Its prevalence is low in Europe, but it should be closely monitored since it seriously limits treatment options.

scholarly journals Constrained Evolution of Human Immunodeficiency Virus Type 1 Protease during Sequential Therapy with Two Distinct Protease Inhibitors

1999 ◽  
Vol 73 (1) ◽  
pp. 850-854 ◽  
Author(s):  
Anne Dulioust ◽  
Sylvie Paulous ◽  
Laurent Guillemot ◽  
Anne-Marie Delavalle ◽  
François Boué ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Sequential Therapy ◽  
Cross Resistance ◽  
Resistance Mutations ◽  
Immunodeficiency Virus ◽  
Constrained Evolution ◽  
Hiv 1

ABSTRACT Human immunodeficiency virus type 1 (HIV-1) variants that have developed protease (PR) inhibitor resistance most often display cross-resistance to several molecules within this class of antiretroviral agents. The clinical benefit of the switch to a second PR inhibitor in the presence of such resistant viruses may be questionable. We have examined the evolution of HIV-1 PR genotypes and phenotypes in individuals having failed sequential treatment with two distinct PR inhibitors: saquinavir (SQV) followed by indinavir (IDV). In viruses where typical SQV resistance mutations were detected before the change to IDV, the corresponding mutations were maintained under IDV, while few additional mutations emerged. In viruses where no SQV resistance mutations were detected before the switch to IDV, typical SQV resistance profiles emerged following the introduction of IDV. We conclude that following suboptimal exposure to a first PR inhibitor, the introduction of a second molecule of this class can lead to rapid selection of cross-resistant virus variants that may not be detectable by current genotyping methods at the time of the inhibitor switch. Viruses committed to resistance to the first inhibitor appear to bear the “imprint” of this initial selection and can further adapt to the selective pressure exerted by the second inhibitor following a pathway that preserves most of the initially selected mutations.

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