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US20100173282A1 - Mutational profile in hiv-1 gag cleavage site correlated with phenotypic drug resistance - Google Patents

Mutational profile in hiv-1 gag cleavage site correlated with phenotypic drug resistance Download PDF

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Publication number
US20100173282A1
US20100173282A1 US12/601,483 US60148308A US2010173282A1 US 20100173282 A1 US20100173282 A1 US 20100173282A1 US 60148308 A US60148308 A US 60148308A US 2010173282 A1 US2010173282 A1 US 2010173282A1
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hiv
gag
drug
mutation
pol
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Inge Dierynck
Sandra De Meyer
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Janssen R&D Ireland ULC
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Tibotec Pharmaceuticals Ltd
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Assigned to TIBOTEC PHARMACEUTICALS LTD. reassignment TIBOTEC PHARMACEUTICALS LTD. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: TIBOTEC BVBA
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    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
    • C12Q1/70—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving virus or bacteriophage
    • C12Q1/701—Specific hybridization probes
    • C12Q1/702—Specific hybridization probes for retroviruses
    • C12Q1/703—Viruses associated with AIDS
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/005—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from viruses
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
    • G01N33/569—Immunoassay; Biospecific binding assay; Materials therefor for microorganisms, e.g. protozoa, bacteria, viruses
    • G01N33/56983—Viruses
    • G01N33/56988—HIV or HTLV
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2740/00—Reverse transcribing RNA viruses
    • C12N2740/00011—Details
    • C12N2740/10011—Retroviridae
    • C12N2740/16011—Human Immunodeficiency Virus, HIV
    • C12N2740/16211—Human Immunodeficiency Virus, HIV concerning HIV gagpol
    • C12N2740/16222—New viral proteins or individual genes, new structural or functional aspects of known viral proteins or genes
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q2600/00—Oligonucleotides characterized by their use
    • C12Q2600/156—Polymorphic or mutational markers
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2333/00—Assays involving biological materials from specific organisms or of a specific nature
    • G01N2333/005—Assays involving biological materials from specific organisms or of a specific nature from viruses
    • G01N2333/08—RNA viruses
    • G01N2333/15—Retroviridae, e.g. bovine leukaemia virus, feline leukaemia virus, feline leukaemia virus, human T-cell leukaemia-lymphoma virus
    • G01N2333/155—Lentiviridae, e.g. visna-maedi virus, equine infectious virus, FIV, SIV
    • G01N2333/16—HIV-1, HIV-2
    • G01N2333/161—HIV-1, HIV-2 gag-pol, e.g. p55, p24/25, p17/18, p.7, p6, p66/68, p51/52, p31/34, p32, p40
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2500/00—Screening for compounds of potential therapeutic value
    • G01N2500/04—Screening involving studying the effect of compounds C directly on molecule A (e.g. C are potential ligands for a receptor A, or potential substrates for an enzyme A)
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2800/00—Detection or diagnosis of diseases
    • G01N2800/52—Predicting or monitoring the response to treatment, e.g. for selection of therapy based on assay results in personalised medicine; Prognosis

Definitions

  • the present invention is directed to the field of nucleic acid diagnostics and the identification of base variation in target nucleic acid sequences.
  • the invention provides novel mutations or mutational profiles of HIV-1 protease cleavage sites (CS) in the Gag region correlated with a phenotype causing alterations in sensitivity to anti-HIV drugs.
  • the present invention also relates to the use of genotypic characterization of a target population of HIV and the subsequent association, i.e. correlation, of this information to phenotypic interpretation in order to correlate virus mutational profiles with drug resistance.
  • the invention further relates to methods of utilizing the mutational profiles of the invention in databases, drug development, i.e., drug design, and drug modification, therapy and treatment design and clinical management.
  • the main target cell for HIV infection was identified as the CD4+ subset of T-cells.
  • HIV In order to replicate, HIV first interacts with cells expressing the CD4 surface protein and co-receptor via binding through the gp120 envelope protein. Following fusion via the gp41 domain of the envelope, entry is achieved, the viral particle degraded and the RNA genome transcribed into double-stranded complementary DNA (cDNA). This genetic material is transported into the cell nucleus as part of the pre-integration complex, where the DNA is processed by viral integrase and incorporated into the host genome. In an activated cell, the viral genome is transcribed and subsequently translated into structural proteins and enzyme precursors.
  • cDNA double-stranded complementary DNA
  • polypeptides Gag and Gag-Pol containing matrix, capsid, nucleocapsid as well as the enzymes reverse transcriptase, protease and integrase are directed to the cell membrane where proteolytic cleavage by viral protease and virion packaging occurs. Most of these events have been extensively studied and a number of stages for possible intervention to prevent viral replication have been identified. These include attachment and entry into the host cell, formation of proviral DNA by reverse transcriptase enzymes, integration of proviral DNA into the host cell chromosomes by integrase, as well as virus assembly, including cleavage of the precursor viral proteins, by viral protease.
  • Clinically relevant agents have been developed against two of these target stages reverse transcription (reverse transcriptase inhibitors (RTI)) and viral assembly (protease inhibitors (PI)).
  • RTI reverse transcriptase inhibitors
  • PI prote inhibitors
  • clinically relevant agents have been developed against fusion/entry of HIV into host cells, but also integrase inhibitors are in clinical development.
  • PIs Protease Inhibitors
  • SQV saquinavir
  • RV ritonavir
  • IDV indinavir
  • NFV nelfinavir
  • AAV amprenavir
  • DDV darunavir
  • HAART highly active antiviral therapy
  • Therapy failure may be due to a number of factors, including insufficient antiviral activity of the regimen, individual variations in drug metabolism and pharma-codynamics, difficulties in adhering to dosing regimen, requirements for treatment interruption due to toxicity, and viral drug resistance. Moreover, drug resistance may develop in a patient treated with sub-optimal antiretroviral therapy or a patient may be infected with drug-resistant HIV-1. Although drug resistance may not be the primary reason for therapy failure, in many cases any situation, which permits viral replication in the presence of an inhibitor, sets the stage for selection of resistant variants.
  • Viral drug resistance can be defined as any change in the virus that improves replication in the presence of an inhibitor. HIV-1 drug resistance was first described in 1989 and involved patients that had been treated with zidovudine monotherapy (Larder, B. A., et al., Science 243, 1731-1734 (1989)).
  • Emergence of resistance is almost always being observed during the course of treatment of patients with single antiretroviral drugs.
  • in vitro passage of viral cultures through several rounds of replication in the presence of antiretroviral compounds leads to the selection of viruses whose replication cycle is no longer susceptible to the antiretroviral compounds used.
  • Resistance development has also been observed with the introduction of dual NRTI combination therapy as well as during the administering of the more potent NNRTIs, PIs and combinations thereof.
  • Individual antiretroviral agents differ in the rate at which resistance develops: selection for resistant variants may occur within weeks of treatment or resistance may emerge after a longer treatment period.
  • K101N refers to replacement of a Lysine at codon 101 with a Asparagine (The Molecular biology of the Cell, 1994, Garland Publishing, NY).
  • the degree of susceptibility of a genetic variant to an antiretroviral compound is expressed herein relative to the wild-type virus (HIV IIIB/LAI reference sequence) as found, for example, in GenBank, the sequence of which is hereby incorporated by reference (K03455, gi 327742, M38432).
  • an alteration in viral drug sensitivity is defined as a change in resistance or a change in susceptibility of a viral strain to said drug.
  • Susceptibilities are generally expressed as ratios of EC 50 or EC 90 values (the EC 50 or EC 90 value being the drug concentration at which 50% or 90% respectively of the viral population is inhibited from replicating) of a viral strain under investigation compared to the wild type strain.
  • the susceptibility of a viral strain can be expressed as a fold change in susceptibility, wherein the fold change is derived from the ratio of for instance the EC 50 values of a mutant viral strain compared to the wild type.
  • the susceptibility of a viral strain or population may also be expressed as resistance of a viral strain, wherein the result is indicated as a fold increase in EC 50 as compared to wild type EC 50 .
  • antiretroviral drugs are administered for longer periods, mostly in combination with each other, and as new antiretrovirals are being developed and added to the present drugs, new resistance-correlated genetic variants are being identified. Of particular importance is that the combination of antiretroviral agents can influence resistance characteristics.
  • the present invention in one aspect, provides a computer system directed by software wherein the software correlates the presence of at least one mutation in the HIV-1 protease cleavage sites in the Gag region (p7/p1 cleavage site) and a change in susceptibility of at least one strain of HIV-1 to a protease inhibitor, more specifically to the combination darunavir/ritonavir.
  • HIV-1 protease catalyses the proteolytic processing of the GAG and GAG-polymerase polyprotein precursors substrate giving rise to the mature structural and enzymatic viral proteins.
  • GAG is expressed as a 55 kDa precursor and is cleaved at the level of 5 sites, p17/p24, p24/p2, p2/p7, p7/p1 and p1/p6, to produce the mature proteins matrix (MA, p17), capsid (CA, p24), p2, nucleocapsid (NC, p7), p1 and p6.
  • MA mature proteins matrix
  • CA capsid
  • NC nucleocapsid
  • the initial cleavage of the 55 kDa GAG precursor by the viral PR takes place at p2/p7, followed by cleavage of secondary p1/p6 and p17/p24, and finally of tertiary p7/p1 and p24/p7.
  • a number of applications describe the occurrence of mutations in HIV and their correlation to the development of drug resistance (WO 00/73511; WO 02/33402; WO 02/22076; WO 00/78996).
  • the instant invention adds to the art a mutation in the gag gene, more specifically in the HIV-1 protease cleavage sites in the gag-region (p7/p1 cleavage site) and its correlation i.e. association to viral drug resistance, more specifically to the combination darunavir/ritonavir.
  • HIV gag mutation is E428G
  • the HIV strain has a decreased susceptibility in combination with other gag and/or protease mutations to at least the combination of darunavir/ritonavir.
  • the invention is drawn to a method of evaluating the effectiveness of antiretroviral therapy more specifically to the combination of darunavir and ritonavir of treatment experienced HIV patients comprising: collecting a sample from an HIV-infected patient; determining whether the sample comprises at least one nucleic acid sequence encoding HIV gag-pol region having at least one mutation E428G in the gag gene and using the presence of the nucleic acid sequence to evaluate the effectiveness of the antiviral therapy.
  • the invention also provides for a method of designing therapy for treating patients infected with HIV comprising: collecting a sample from an HIV-infected patient; determining whether the sample comprises at least one nucleic acid sequence encoding HIV gag-pol region having at least one mutation E428G in the gag gene described herein; and using the presence of the nucleic acid sequence to design a therapy for the patient.
  • a change in effectiveness can be expressed as a fold change in resistance.
  • the fold change may be determined using a cellular assay including the cytopathogenic assay or the Antivirogram® (WO 97/27480).
  • the fold change in susceptibility may be derived from database analysis such as the VircoTYPE HIV-1TM (WO 01/79540).
  • a decrease in susceptibility vis-à-vis the wild type virus correlates to an increased viral drug resistance, and hence reduced effectiveness of said drug.
  • the activity of the mutant enzyme may be compared to the activity of a wild type enzyme. In phenotyping assays pseudotyped viruses may be used.
  • the mutations present in HIV gag-pol region may be determined at the nucleic acid or amino acid level using sequencing or hybridization techniques.
  • a report may be generated that shows the region of the patient virus that has been sequenced, including at least one mutation E428G.
  • the report may include antiretroviral drugs, drug(s) for which a known resistance-associated mutation has been identified and/or to what extent the observed mutation(s) selected from at least E428G are indicative of resistance to drugs.
  • the sample to be evaluated can be a bodily fluid including blood, serum, plasma, saliva, urine, or a tissue including gut tissues.
  • a drug effective against a mutant in HIV gag-pol region may be identified by a method, comprising: (i) providing a nucleic acid sequence comprising HIV gag-pol region comprising at least one mutation E428G in the gag gene; (ii) determining a phenotypic response to said drug for said HIV recombinant virus; and (iii) identifying a drug effective against mutant HIV based on the phenotypic response of step (ii).
  • the nucleic acid sequence comprising HIV of step (i) may be recombined into a proviral nucleic acid sequence deleted for said sequence to generate a recombinant HIV virus.
  • Identifying a drug is defined as making a selection of drugs clinically available based on the effectiveness of said drug. In addition to the selection of clinically available drugs identifying also relates to the selection of clinical drug candidates.
  • the phenotypic response may be determined using cellular assays such as the Antivirogram®.
  • An effective drug against mutant HIV comprising at least one mutation E428G in the gag region or gag gene is defined as a drug having a phenotypic response expressed, as e.g. a fold change in susceptibility lower than a defined cut-off that may be determined for a drug.
  • Another useful method for identifying, a drug effective against a mutant in HIV gag-pol region comprises: (i) providing a HIV gag-pol region comprising at least one mutation E428G in the gag gene, (ii) determining the activity of said drug on said HIV gag-pol region; (iii) determining the activity of said drug on wild type HIV gag-pol region; (iv) determining the ratio of the activity determined in step (iii) over the activity determined in step (ii); (v) identifying an effective drug against the mutant HIV based on the ratio of step (iv).
  • a ratio lower than a defined cut-off value that can be specific for said drug is indicative that the drug is effective against mutant HIV (WO 02/33402).
  • Resistance of HIV to antiretroviral drugs may be determined at the genotypic level by identifying mutations in the HIV-1 genome and by inferring the resistance of HIV-1 to antiretroviral drugs through searching for mutational patterns known to correlate with resistance.
  • Assays for detection of mutations in HIV-1 may be based on polymerase chain reaction (PCR) amplification of viral genomic sequences. These amplified sequences are then analyzed using either hybridization or sequencing techniques.
  • Hybridization-based assays include primer-specific PCR, which makes use of synthetic oligonucleotides designed to allow selective priming of DNA synthesis. See Larder, B. A., et al., AIDS 5, 137-144 (1991); Richman, D. D., et al., J.
  • Phenotyping assays measure the ability of a replicating virus to grow in the presence of compounds compared to a wild-type reference virus such as e.g. HIV-1/LAI, HIV-1/NL4.3, HIV-1/HXB2 or e.g. HIV-2/ROD.
  • phenotyping assays are performed with pseudotyped viruses not able to replicate (WO 02/38792). Consequently, these assays directly measure the degree of viral susceptibility to specific inhibitors. In this case, one measures the effect of all mutational interactions, the effects of genetic changes as yet unknown or not previously identified, the effect of the background genotype, etc., on the phenotype.
  • Virologic response was defined as viral load ⁇ 50 copies/mL at week 24. Mutations in the 5 Gag CS were determined at baseline and confirmed point of rebound and/or a later time point within the treatment phase.
  • GAG genotypic analysis was performed on virus isolates from subjects of pooled trials. All subjects included in the Week 96 efficacy analysis and Week 48 efficacy analysis of said trails, who received the recommended dose of DRV/rtv 600/100 mg b.i.d. starting from Day 1, were included in this analysis.
  • Virological failures were defined using the TLOVR non-virologic failure (VF)-censored algorithm in which the responses at time points after discontinuation are not imputed (i.e. left missing) for patients who drop for reasons other than virologic failures.
  • VF non-virologic failure
  • patients that drop out for reasons other than virologic failure are not automatically considered as rebounders or non-responders.
  • patients who did not have the chance to respond were not taken into account to determine rebound or non-response.
  • Genotypic analyses were performed by automated population-based sequencing. Sequence data were aligned to the wildtype HIV-1/HXB2 CG reference and reported as amino acid changes along GAG and PR. Genotypic mixtures (a combination of different amino acids at 1 position) were reported. Amino acids were presented with their one letter code. Mutations in the 5 PR cleavage sites in the GAG region, encompassing the amino acids 128-137 (p17/p24), 359-368 (p24/p2), 373-382 (p2/p7), 428-437 (p7/p1), and 444-453 (p1/p6), were reported.
  • Genotypes PR and reverse transcriptase [RT] were determined by default on plasma samples taken at predefined time points (e.g. screening, Week ⁇ 2, baseline, Week 2, Week 24, Week 48, Week 96, Week 144 and final/withdrawal visit) when the viral load was >1000 HIV-1 RNA copies/mL. Furthermore, samples at other time points, such as confirmed virologic failure, were also analyzed upon request of the protocol virologist. GAG genotypic analysis was determined at baseline and confirmed point of rebound and/or a later time point within the treatment phase.
  • Endpoint could be a time point pre-defined in the protocol to perform a genotype or a time point at which a genotype was requested by the protocol virologist, e.g. at the time of virologic failure.
  • Recombinant HIV-1 clinical isolates were constructed according to the Antivirogram® method. Briefly, PR and RT coding sequences were amplified from patient-derived viral RNA with HIV-1 specific primers. After homologous recombination of amplicons into a PR-RT deleted proviral clone, the resulting recombinant viruses were harvested and used for in vitro susceptibility testing.
  • Virologic response was defined using the TLOVR non-VF censored algorithm eliminating patients who had no chance to respond (discontinuation before Week 16).
  • Virologic response was defined using the TLOVR, non-VF censored algorithm eliminating patients who had no chance to respond (discontinuation before Week 16), resulting in 445 subjects included in the analysis.
  • endpoints including the primary endpoint (proportion of responders with confirmed 1.0 log 10 decrease in viral load at Week 24), change in viral load from baseline at Week 24 and proportion of responders with viral load ⁇ 50 HIV-1 RNA copies/mL at Week 24 were evaluated.
  • virologic outcomes were examined in 3 separate groups: all subjects (All), subjects who did not use ENF (enfuvirtide) or who used ENF currently and received ENF in their previous therapy (no/non-na ⁇ ve ENF), and subjects who started ENF for the first time (ENF na ⁇ ve) in the trials.
  • the focus was on the no/non-na ⁇ ve ENF group to assess baseline resistance predictors of response to DRV/rtv treatment without the additive effect of ENF use.
  • Virologic response was defined in 3 different ways (decrease of 1.0 log 10 in plasma viral load versus baseline, change versus baseline in log 10 viral load, or viral load ⁇ 50 HIV-1 RNA copies/mL), and diminished response was defined as response rates ⁇ 75% of the overall response rate or mean changes versus baseline in viral load ⁇ 1.0 log 10 .
  • TABLE 1 Virologic Response Rate (TLOVR, non-VF Censored) Defined as a Decrease ⁇ 1.0 log 10 in Plasma Viral Load Versus Baseline at Week 24 by Presence of Individual PR Cleavage Site Mutations in GAG at Baseline DRV/rtv 600/100 mg b.i.d.
  • TLOVR Virologic Response Rate

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US12/601,483 2007-05-25 2008-05-23 Mutational profile in hiv-1 gag cleavage site correlated with phenotypic drug resistance Abandoned US20100173282A1 (en)

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PCT/EP2008/056356 WO2008145606A1 (fr) 2007-05-25 2008-05-23 Nouveau profil mutationnel dans un site de clivage du gag du vih-1 corrélé à une résistance phénotypique aux médicaments

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Cited By (2)

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US20110320597A1 (en) * 2010-06-24 2011-12-29 Michael South Systems and methods for terminating communication requests in an internet protocol environment
WO2013052947A1 (fr) * 2011-10-06 2013-04-11 The Johns Hopkins University Peptides rétroviraux de jonction et leur utilisation pour identifier de nouvelles cibles pour des médicaments anti-rétroviraux

Citations (1)

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US20120258448A1 (en) 2012-10-11
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US8546076B2 (en) 2013-10-01
US20140127797A1 (en) 2014-05-08

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