Methods for measuring therapy resistance

• US 7,206,699 B2
• Filed: 04/18/2001
• Issued: 04/17/2007
• Est. Priority Date: 04/18/2000
• Status: Expired due to Fees

• Current Assignee: Virco BVBA (Johnson & Johnson)
• Original Assignee: Virco NV
• Inventors: Hertogs, Kurt, Larder, Brendan, Mortier, Rudy Jean Marc, Dehertogh, Pascale Alfons Rosa, Bloor, Stuart
• Primary Examiner(s): Clow; Lori A.
• Application Number:
  US09/836,477
• Publication Number:
  US 20020091664A1
• Time in Patent Office: 2,190 Days
• Field of Search: 702/19, 702/20, 702/22
• US Class Current: 702/19
• CPC Class Codes: A61P 31/18 for HIV
• CPC Class Codes: C12Q 1/6876 Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes
• CPC Class Codes: C12Q 1/703 Viruses associated with AIDS
• CPC Class Codes: C12Q 1/707 non-A, non-B Hepatitis, excluding hepatitis D
• CPC Class Codes: C12Q 2600/156 Polymorphic or mutational markers
• CPC Class Codes: G16B 20/00 ICT specially adapted for functional genomics or proteomics, e.g. genotype-phenotype associations
• CPC Class Codes: G16B 30/00 ICT specially adapted for sequence analysis involving nucleotides or amino acids
• CPC Class Codes: G16B 30/10 Sequence alignment; Homology search
• CPC Class Codes: G16B 40/00 ICT specially adapted for biostatistics; ICT specially adapted for bioinformatics-related machine learning or data mining, e.g. knowledge discovery or pattern finding
• CPC Class Codes: G16B 40/20 Supervised data analysis
• CPC Class Codes: G16B 50/00 ICT programming tools or database systems specially adapted for bioinformatics
• CPC Class Codes: G16B 50/20 Heterogeneous data integration

Abstract

The present invention concerns methods for measuring drug resistance by correlating genotypic information with phenotypic profiles. In one embodiment, a method for interpreting genotypic information is described wherein a genetic code is generated from a patient sample, a list of mutations known or suspect to play a role in the development of resistance to one or more drugs is obtained from the generated genetic code, a genotype database is interrogated for previous samples with similar mutations relating to said one or more drugs, a phenotype for said sample is located in a phenotype database, the mean change in inhibition is determined based on all the examples located in said phenotype database, a distribution of sensitivities of one or more drugs suitable for treating a specific indication is determined.

Claims

1. A method of determining a phenotype of a retrovirus, wherein the retrovirus is the Human Immunodeficiency Virus, comprising:

a) obtaining from a patient a sample comprising at least one of a plasma sample, a blood sample, a saliva sample, mucous sample, and a tissue sample;

b) obtaining a genetic sequence of the Human Immunodeficiency Virus from the patient sample;

c) identifying a mutation pattern of the genetic sequence of the Human Immunodeficiency Virus, wherein said mutation pattern comprises at least one mutation that correlates to resistance to at least one therapy;

d) searching a relational genotype/phenotype database for at least one database mutation pattern similar to said mutation pattern of the genetic sequence of the Human Immunodeficiency Virus;

e) obtaining at least one database phenotype of the at least one database mutation pattern; and

f) determining the phenotype of the Human Immumunodeficiency Virus from the at least one database phenotype.

2. The method of claim 1, wherein a series of phenotypes is obtained by repeating steps b) through e) for each therapy in a group of therapies.

3. The method of claim 1, wherein said mutation pattern of the genetic sequence of the Human Immunodeficiency Virus is specific to a therapy.

4. The method of claim 1, wherein said at least one mutation is chosen from a frame shift mutation, a base substitution, and an epigenetic mutation.

5. The method of claim 1, wherein the genetic sequence of Human Immunodeficiency Virus is the genetic sequence of the protease region of the Human Immunodeficiency Virus genome, the genetic sequence of the reverse transcriptase region of the Human Immunodeficiency Virus genome, or the genetic sequence of the protease region and reverse transcriptase region of the Human Immunodeficiency Virus genome.

6. The method of claim 1, wherein said mutation pattern of the genetic sequence of the Human Immunodeficiency Virus comprises at least two mutations that correlate to resistance to at least one therapy.

7. The method of claim 1, wherein the search of the relational genotype/phenotype database for at least one sample with a similar mutation pattern uses cluster searches.

8. The method of claim 1, wherein the database mutation pattern comprises at least one mutation found in said mutation pattern of the genetic sequence of the Human Immunodeficiency Virus.

9. The method of claim 1, wherein the database mutation pattern is a mutation pattern in which at least about 50% of the mutations are identical to said mutation pattern of the genetic sequence of the Human Immunodeficiency Virus.

10. The method of claim 9, wherein the database mutation pattern is a mutation pattern in which at least about 80% of the mutations are identical to said mutation pattern of the genetic sequence of the Human Immunodeficiency Virus.

11. The method of claim 10, wherein the database mutation pattern is a mutation pattern in which at least about 90% of the mutations are identical to said mutation pattern of the genetic sequence of the Human Immunodeficiency Virus.

12. The method of claim 11, wherein the mutations of the database mutation pattern are identical to said mutation pattern of the genetic sequence of the Human Immunodeficiency Virus.

13. The method of claim 1, wherein the phenotype of the Human Immunodeficiency Virus is a mean fold-change in resistance, wherein said mean fold change is obtained from all of the database phenotypes obtained in step d).

14. The method of claim 1, wherein the phenotype of the Human Immunodeficiency Virus is expressed as an IC₅₀.

15. A method of reporting a phenotype for a Human Immunodeficiency Virus, comprising generating a report having the phenotype determined using the method of claim 1.

16. A method of determining a phenotype of a retrovirus, wherein the retrovirus is the Human Immunodeficiency Virus comprising:

a) obtaining from a patient a sample comprising at least one of a plasma sample, a blood sample, a saliva sample, mucous sample, and a tissue sample;

b) obtaining a genetic sequence of the Human Immunodeficiency Virus from the patient sample;

c) searching a relational genotype/phenotype database for at least one database genetic sequence similar to said genetic sequence of the Human Immunodeficiency Virus;

d) obtaining a database phenotype of the at least one database genetic sequence; and

e) determining the phenotype of the Human Immunodeficiency Virus from the database phenotype.

17. The method of claim 16, wherein the at least one database genetic sequence is at least about 60% identical to the genetic sequence of the Human Immunodeficiency Virus.

18. The method of claim 17, wherein the at least one database genetic sequence is at least about 70% identical to the genetic sequence of the Human Immunodeficiency Virus.

19. The method of claim 18, wherein the at least one database genetic sequence is at least about 80% identical to the genetic sequence of the Human Immunodeficiency Virus.

20. The method of claim 19, wherein the at least one database genetic sequence is at least about 90% identical to the genetic sequence of the Human Immunodeficiency Virus.

21. A computer program for determining a phenotype of a retrovirus, wherein the retrovirus is the Human Immunodeficiency Virus, wherein the program is comprised on a computer readable medium, comprising:

a) receiving a genetic sequence from the Human Immunodeficiency Virus from a patient;

b) identifying a mutation pattern of the genetic sequence of the Human Immunodeficiency Virus, wherein said mutation pattern comprises at least one mutation that correlates to resistance to at least one therapy;

c) searching a relational genotype/phenotype database for at least one database mutation pattern similar to said mutation pattern of the genetic sequence of the Human Immunodeficiency Virus;

d) obtaining at least one database phenotype of the at least one database mutation pattern from the relational genotype/phenotype database;

e) determining the at least one phenotype of Human Immunodeficiency Virus from the at least one database phenotype; and

f) displaying the phenotype of the Human Immunodeficiency Virus sample.

22. The computer program of claim 21, wherein a series of phenotypes is obtained by repeating steps b) through e) for a group of therapies.

23. The computer program of claim 22, wherein the phenotype of the Human Immunodeficiency Virus is provided in a report.