WO2002099387A2 - Dispositif et methodes de surveillance d'une therapie antiretrovirale inhibitrice de la protease et determination de decisions therapeutiques dans le traitement du vih/sida - Google Patents

Dispositif et methodes de surveillance d'une therapie antiretrovirale inhibitrice de la protease et determination de decisions therapeutiques dans le traitement du vih/sida Download PDF

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Publication number
WO2002099387A2
WO2002099387A2 PCT/US2002/018684 US0218684W WO02099387A2 WO 2002099387 A2 WO2002099387 A2 WO 2002099387A2 US 0218684 W US0218684 W US 0218684W WO 02099387 A2 WO02099387 A2 WO 02099387A2
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Prior art keywords
mutation
codon
hiv
patient
protease
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PCT/US2002/018684
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English (en)
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WO2002099387A3 (fr
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Neil T. Parkin
Rainer A. Zeirmann
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Virologic, Inc.
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Publication date
Priority claimed from US09/874,472 external-priority patent/US20030108857A1/en
Priority claimed from PCT/US2002/001682 external-priority patent/WO2002068618A1/fr
Application filed by Virologic, Inc. filed Critical Virologic, Inc.
Priority to EP02744311A priority Critical patent/EP1407042A4/fr
Publication of WO2002099387A2 publication Critical patent/WO2002099387A2/fr
Publication of WO2002099387A3 publication Critical patent/WO2002099387A3/fr

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    • 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
    • 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
    • C12Q1/34—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving hydrolase
    • C12Q1/37—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving hydrolase involving peptidase or proteinase
    • 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
    • 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
    • C12N2740/16041—Use of virus, viral particle or viral elements as a vector
    • C12N2740/16043—Use of virus, viral particle or viral elements as a vector viral genome or elements thereof as genetic vector
    • 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
    • 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
    • G01N2500/10—Screening for compounds of potential therapeutic value involving cells

Definitions

  • Decreased susceptibility to protease inhibitors, such as indinavir and saquinavir, in viruses containing L90M was observed in viruses with additional mutations at secondary positions, such as, 73, 71, 77, and/or 10 as described herein.
  • Decreased susceptibility to protease inhibitors, such as indinavir and saquinavir, in viruses containing L90M was also observed in viruses with at least 3 or more additional mutations at secondary positions.
  • the mutations were found in plasma HIV nucleic acid after a period of time following the initiation of therapy. The development of these mutations, or combinations of these mutations, in HIV PR was found to be an indicator of the development of alterations in phenotypic susceptibility/resistance, which can be associated with virologic failure and subsequent immunological response.
  • Phenotypic PRI susceptibility profile of a protease mutant generated by site-specific oligonucleotide-directed mutagenesis was carried out giving the phenotypic drug susceptibility profile of a virus having substitutions at codons 63, 77 -JJ-
  • a mutation at codon 88 to a serine residue of HIV protease is correlated with an increase in amprenavir susceptibility and a mutation at codon 88 to a serine residue in combination with mutations at codons 46, 63 and/or 77 or a combination thereof of HIV protease are correlated with an increase in amprenavir susceptibility and a decrease in nelfinavir and indinavir susceptibility.
  • codon number refers to the position of the amino acid that the codon codes for. Therefore a codon referencing a particular number is equivalent to a "postion" referencing a particular number, such as for example, "codon 88" or "position 88".
  • Another preferred, non-limiting, specific embodiment of the invention is as follows: a method of evaluating the effectiveness of antiretroviral therapy of an HIV-infected patient comprising: (a) collecting a biological sample from an HIV-infected patient; and (b) determining whether the biological sample comprises nucleic acid encoding HIV protease having a mutation at codon 88 to serine and additional mutation (s) at codons 63, 77 and/or 46 or a combination thereof.
  • Resistance test vector means one or more vectors which taken together contain DNA comprising a patient-derived segment and an indicator gene. Resistance test vectors are prepared as described in US Patent Number 5,837,464
  • the method is provided , wherein the mutation at codon 82 is a substitution of alanine (A), phenylalanine (F), serine (S), or threonine (T) for valine (V) .
  • the method is provided, wherein the mutation at codon 90 codes for methionine (M) .
  • the method is provided , wherein the mutation at codon 90 is a substitution of methionine (M) for leucine (L) .
  • the above method is provided of assessing the effectiveness of protease antiretroviral therapy, wherein the mutation at codon 82 is a substitution of alanine (A), phenylalanine (F) , serine (S), or threonine (T) for valine (V) and the mutation at codon 90 is a substitution of methionine (M) for leucine (L) .
  • Target Host Cell - a host cell to be infected by a resistance test vector viral particle produced by the resistance test vector host cell
  • the indicator gene may be capable of being expressed in a "packaging host cell/resistance test vector host cell" as defined below, independent of the patient-derived segment, however the functional indicator gene could not be expressed in the target host cell, as defined below, without the production of functional resistance test vector particles and their effective infection of the target host cell.
  • the indicator gene cassette comprising control elements and a gene encoding an indicator protein, is inserted into the indicator gene viral vector with the same or opposite transcriptional orientation as the native or foreign enhancer/promoter of the viral vector.
  • a preferred embodiment for an HIV drug susceptibility and resistance test is to place the genomic or subgenomic viral coding regions under the control of the native enhancer/promoter of the HIV-LTR U3 region or the CMV immediate-early (IE) enhancer/promoter.
  • a preferred embodiment for an HBV drug susceptibility and resistance test is to place the genomic or subgenomic viral coding regions under the control of the CMV immediate-early (IE) enhancer/promoter.
  • an indicator gene viral vector that contains one or more viral genes which are the targets or encode proteins which are the targets of an anti-viral drug(s) then said vector contains the patient sequence acceptor sites.
  • the patient-derived segments are inserted m the patient sequence acceptor site m the indicator gene viral vector which is then referred to as the resistance test vector, as described above.
  • Preferred host cells for use as target host cells include human T cell leukemia cell lines including Jurkat (ATCC T1B-152), H9 (ATCC HTB-176), CEM (ATCC CCL-119), HUT78 (ATCC T1B-161), and derivatives tnereof.
  • the IC50 values were determined by plotting percent drug inhibition vs. log :0 drug concentration.
  • This panel of anti-retroviral drugs comprised members of the classes known as NRTIs (AZT, 3TC, d4T, ddl, ddC, and abacavir) , NNRTIs (delavirdine, . nevirapine and efavirenz), and PRIs (indinavir, nelfinavir, ritonavir, saquinavir and amprenavir) .
  • An IC50 was determined for each drug tested. Susceptibility of the patient virus to each drug was examined and compared to known patterns of susceptibility.
  • a pattern of susceptibility to the PRIs was observed for patient sample RTV-3654 in which there was a decrease in indinavir and nelfinavir susceptibility (increased resistance) and an increase in amprenavir susceptibility.
  • Patient sample 3654 was examined further for genotypic changes associated with the pattern of susceptibility.
  • Saquinavir resistance in viruses containing mutations at position 90 was evaluated with respect to the presence of other specific mutations. Decreased saquinavir susceptibility (fold-change IC 50 greater than 2.5) viruses containing L90M but no other primary mutations was correlated with the presence of mutations at secondary positions. Reduced saquinavir susceptibility was observed in 15 of IS samples containing mutations at both positions 73 and 90 (79%) and m 14 of 18 samples with both 71 and 90 (78%) (See Table 11) . The combination of mutations at position 90 with mutations at other positions (e.g. 77 and 10) also significantly increased the proportion of samples that had reduced saquinavir susceptibility (Table 1) .
  • EXAMPLE 9 Predicting Response to Protease Inhibitors by Characterization of Amino Acids 82 and 90 of HIV-1
  • evaluation of protease inhibitor susceptibility and of whether amino acid positions 82 and 90 of HIV-1 protease was wild type or alanine, phenylalanine, serine, or threonine in the case of position 82 and methionine at position 90 was carried out using a phenotypic susceptibility assay or genotypic assay, respectively, using resistance test vector DNA prepared from the biological sample.
  • plasma sample was collected, viral RNA was purified and an RT-PCR methodology was used to amplify a patient derived segment encoding the HIV-1 protease and reverse transcriptase regions.
  • Protease inhibitor susceptibility of viruses containing mutations at amino acids 82 and 90 of HIV-1 Protease Phenotypic susceptibility profiles of 33 patient virus samples which contained mutations at positions 82 (V82A, F, S, or T) and 90 (L90M) , but no other primary mutations, were analyzed. According to most published guidelines, such viruses are expected to be resistant to ritonavir, nelfinavir, indinavir, and saquinavir. However, 9% and 21% of these samples were phenotypically susceptible to indinavir and saquinavir, respectively (see Table 6) . Thus, particularly for saquinavir, there was poor correlation between the presence of mutations at positions 82 and 90 and drug susceptibility.
  • This example provides the means and methods for identifying mutations that alter replication fitness for various components of HIV-1 replication, including, but not limited to integration, virus assembly, and virus attachment and entry.
  • This example also provides a means and method for quantifying the affect that specific mutations in protease or reverse transcriptase have on replication fitness. This method can be used for quantifying the effect that specific protease mutations have on replication fitness and can be used to quantify the effect of other mutations in other viral genes involved in HIV-1 replication, including, but not limited to the gag, pol, and envelope genes.
  • Fitness test vectors were constructed as described in example 10.
  • protease mutations D30N, M46I/L, G48V, I54L/A/S/T/V, and I84V were observed at high incidences in viruses with reduced protease processing of the p55 gag polyprotein (Figure L) .
  • Amplification of the HIV-1 nucleic acid can be performed using a variety of methodologies including reverse transcription-polymerase chain reaction (RT-PCR) , NASBA, SDA, RCR, or 3SR.
  • RT-PCR reverse transcription-polymerase chain reaction
  • the nucleic acid sequence encoding HIV protease at codon 82 can be determined by direct nucleic acid sequencing using various primer .extension-chain termination (Sanger, ABI/PE and Visible Genetics) or chain cleavage (Maxam and Gilbert) methodologies or more recently developed sequencing methods such as matrix assisted laser desorption-ionization time of flight (MALDI-TOF) or mass spectrometry (Sequenom, Gene Trace Systems).
  • MALDI-TOF matrix assisted laser desorption-ionization time of flight
  • MSequenom Gene Trace Systems
  • the above method is provided of assessing the effectiveness of protease antiretroviral therapy, having a mutation at codon 82 and a secondary mutation at codon 13, or a mutation at codon 90 and a secondary mutation at codon 74, wherein the change in susceptibility in step (c) is an increase in susceptibility to indinavir.

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  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Wood Science & Technology (AREA)
  • Virology (AREA)
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  • Engineering & Computer Science (AREA)
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  • Bioinformatics & Cheminformatics (AREA)
  • General Engineering & Computer Science (AREA)
  • Physics & Mathematics (AREA)
  • AIDS & HIV (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Medicinal Chemistry (AREA)
  • Measuring Or Testing Involving Enzymes Or Micro-Organisms (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

L'invention concerne des essais de prédisposition et de résistance à un médicament antiviral qu'on utilise pour identifier des régimes posologiques efficaces dans le traitement d'une infection au virus de l'immunodéficience humaine (VIH) et du syndrome immunodéficitaire acquis (SIDA), notamment des régimes posologiques comportant un inhibiteur de la protéase. Cette invention a également trait à un dispositif et des méthodes de surveillance de la progression clinique de l'infection au VIH et de sa réponse à une thérapie antirétrovirale utilisant des dosages de prédisposition phénotypique ou génotypique.
PCT/US2002/018684 2001-06-04 2002-06-04 Dispositif et methodes de surveillance d'une therapie antiretrovirale inhibitrice de la protease et determination de decisions therapeutiques dans le traitement du vih/sida WO2002099387A2 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
EP02744311A EP1407042A4 (fr) 2001-06-04 2002-06-04 Dispositif et methodes de surveillance d'une therapie antiretrovirale inhibitrice de la protease et determination de decisions therapeutiques dans le traitement du vih/sida

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US09/874,472 2001-06-04
US09/874,472 US20030108857A1 (en) 2001-06-04 2001-06-04 Means and methods for monitoring protease inhibitor antiretroviral therapy and guiding therapeutic decisions in the treatment of HIV/AIDS
USPCT/US02/01682 2002-01-18
PCT/US2002/001682 WO2002068618A1 (fr) 2001-01-19 2002-01-18 Procedes pour controler une therapie antiretrovirale par inhibiteur de protease

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WO2002099387A2 true WO2002099387A2 (fr) 2002-12-12
WO2002099387A3 WO2002099387A3 (fr) 2003-04-24

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Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6869759B1 (en) 1999-06-22 2005-03-22 Virologic, Inc. Means and methods for monitoring protease inhibitor antiretroviral therapy and guiding therapeutic decisions in the treatment of HIV/AIDS
US7138231B2 (en) 2000-09-15 2006-11-21 Monogram Biosciences, Inc. Means and methods for monitoring protease inhibitor antiretroviral therapy and guiding therapeutic decisions in the treatment of HIV/AIDS
EP1726643A1 (fr) * 2005-05-27 2006-11-29 Direvo Biotech AG Méthode pour la provision, l'identification, la sélection des protéases avec une sensititivité modifiée contre des substances modulatrices
US7186506B1 (en) 2000-06-12 2007-03-06 Monogram Biosciences, Inc. Means and methods for monitoring protease inhibitor antiretroviral therapy and guiding therapeutic decisions in the treatment of HIV/AIDS
US7384734B2 (en) 2002-02-15 2008-06-10 Monogram Biosciences, Inc. Compositions and methods for determining the susceptibility of a pathogenic virus to protease inhibitors
US7553618B2 (en) 2002-07-01 2009-06-30 Monogram Biosciences, Inc. Method for determining human immunodeficiciency virus type 1 (HIV-1) hypersusceptibility to the protease inhibitor amprenavir
WO2010063411A1 (fr) * 2008-12-01 2010-06-10 Roche Diagnostics Gmbh Système et procédé pour la détection de variants d’intégrase de vih
US7993824B2 (en) 2002-07-01 2011-08-09 Monogram Biosciences, Inc. Compositions and methods for determining the susceptibility of a pathogenic virus to protease inhibitors

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AU5758200A (en) * 1999-06-22 2001-01-09 Virologic, Inc. Means and methods for monitoring protease inhibitor antiretroviral therapy and guiding therapeutic decisions in the treatment of hiv/aids

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
See also references of EP1407042A2 *
ZIERMANN ET AL.: 'A mutation in human immunodeficiency virus type 1 protease, N88S, that causes in vitro hypersensitivity to amprenavir' J. VIROLOGY vol. 74, no. 9, May 2000, pages 4414 - 4419, XP002908352 *

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6869759B1 (en) 1999-06-22 2005-03-22 Virologic, Inc. Means and methods for monitoring protease inhibitor antiretroviral therapy and guiding therapeutic decisions in the treatment of HIV/AIDS
US7186506B1 (en) 2000-06-12 2007-03-06 Monogram Biosciences, Inc. Means and methods for monitoring protease inhibitor antiretroviral therapy and guiding therapeutic decisions in the treatment of HIV/AIDS
US7138231B2 (en) 2000-09-15 2006-11-21 Monogram Biosciences, Inc. Means and methods for monitoring protease inhibitor antiretroviral therapy and guiding therapeutic decisions in the treatment of HIV/AIDS
US7384734B2 (en) 2002-02-15 2008-06-10 Monogram Biosciences, Inc. Compositions and methods for determining the susceptibility of a pathogenic virus to protease inhibitors
US7553618B2 (en) 2002-07-01 2009-06-30 Monogram Biosciences, Inc. Method for determining human immunodeficiciency virus type 1 (HIV-1) hypersusceptibility to the protease inhibitor amprenavir
US7993824B2 (en) 2002-07-01 2011-08-09 Monogram Biosciences, Inc. Compositions and methods for determining the susceptibility of a pathogenic virus to protease inhibitors
EP1726643A1 (fr) * 2005-05-27 2006-11-29 Direvo Biotech AG Méthode pour la provision, l'identification, la sélection des protéases avec une sensititivité modifiée contre des substances modulatrices
WO2010063411A1 (fr) * 2008-12-01 2010-06-10 Roche Diagnostics Gmbh Système et procédé pour la détection de variants d’intégrase de vih

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Publication number Publication date
EP1407042A2 (fr) 2004-04-14
EP1407042A4 (fr) 2006-02-22
WO2002099387A3 (fr) 2003-04-24

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