Mutational profiles in hiv-1 reverse transcriptase correlated with phenotypic drug resistance

Abstract

The invention provides novel mutations, mutation combinations or mutational profiles of HIV-1 reverse transcriptase and/or protease genes correlated with phenotypic resistance to HIV drugs. More particularly, the present invention relates to the use of genotypic characterization of a target population of HIV and the subsequent correlation of this information to phenotypic interpretation in order to correlate virus mutational profiles with drug resistance. The invention also 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, clinical management and diagnostic analysis.

1 . A computer system comprising at least one database chosen from: 
 (i) a database correlating the presence of at least one mutation in a human immunodeficiency virus (HIV) reverse transcriptase and resistance of at least one strain of HIV to a reverse transcriptase inhibitor, comprising at least one set of records chosen from: 
 a set of records corresponding to a correlation between at least one mutation chosen from 44D, 77L, 115F, 118I, 184V, 208Y, 210W, 211K, 214F, 215F, 215Y, 219E, 219N, and 219Q, and resistance to d4T;  
 a record corresponding to a correlation between mutation 184I and resistance towards lamivudine;  
 a set of records corresponding to a correlation between at least one mutation chosen from 115F and 184V and resistance towards abacavir;  
 a record corresponding to a combination of 62V, 75T, 77L, 116Y and 151M and resistance towards all nucleoside analogues;  
 a set of records corresponding to a correlation between at least one mutation chosen from 101H, 101P, 103H, 103S, 103T, 106M, 181S, and 190Q and resistance towards nevirapine;  
 a set of records corresponding to a correlation between at least one mutation chosen from 101H, 101P, 103H, 103N, 103S, 103T, 106M, 181C, 181S and 190Q and resistance towards delavirdine;  
 a set of records corresponding to a correlation between at least one mutation chosen from 101H, 101P, 103H, 103S, 103T, 106M, 181S, 190Q and 236L and resistance towards efavirenz;  
 a record corresponding to a combination of 184V and 41L and 215Y, wherein the 184V resistance mutation reverses the effect of 41L and 215Y mutations on zidovudine;  
 a record corresponding to a 236L mutation, which increases the sensitivity towards nevirapine;  
   (ii) a database correlating the presence of at least one mutation in a human immunodeficiency virus (HIV) protease and resistance of at least one strain of HIV to a protease inhibitor, comprising a set of records corresponding to a correlation between at least mutation selected from 54L, 54M, 54V and any mutation at codon 84 and resistance towards a protease inhibitor.    
     
     
         2 . A computer system according to  claim 1  wherein the mutation at codon 84 is selected from 84A, 84C and 84L.  
     
     
         3 . A computer system according to any one of  claims 1  to  2  wherein the protease inhibitor is selected from amprenavir, saquinavir, nelfinavir, ritonavir and indinavir.  
     
     
         4 . A computer system according to any one of  claims 1  to  3  wherein the at least one mutation in the HIV protease is combined with at least one mutation in the HIV protease at codon 10 and/or codon 90.  
     
     
         5 . A computer system according to any one of  claims 1  to  4  wherein the at least one mutation in the HIV protease is combined with at least one mutation in the HIV protease selected from 10I, 20R, 20T, 24I, 33F, 33I, 33L, 36I, 46L, 71T, 71V, 77I, 77V, 82I, 82V or 90M.  
     
     
         6 . A method of evaluating the effectiveness of d4T as an antiviral therapy of an HIV-infected patient comprising: 
 (a) collecting a sample from an HIV-infected patient;    (b) determining whether the sample comprises a nucleic acid encoding a HIV reverse transcriptase having at least one mutation chosen from 44D, 77L, 115F, 118I, 184V, 208Y, 210W, 211K, 214F, 215F, 215Y, 219E, 219N, and 219Q;    (c) using the presence of said at least one mutation of step b) to evaluate the effectiveness of said antiviral therapy.    
     
     
         7 . A method of evaluating the effectiveness of lamivudine as an antiviral therapy of an HIV-infected patient comprising: 
 (a) collecting a sample from an HIV-infected patient;    (b) determining whether the sample comprises a nucleic acid encoding a HIV reverse transcriptase having at least the mutation 184I;    (c) using the presence of said at least one mutation of step b) to evaluate the effectiveness of said antiviral therapy.    
     
     
         8 . A method of evaluating the effectiveness of abacavir as an antiviral therapy of an HIV-infected patient comprising: 
 (a) collecting a sample from an HIV-infected patient;    (b) determining whether the sample comprises a nucleic acid encoding a HIV reverse transcriptase having at least one mutation chosen from 115F and 184V;    (c) using the presence of said at least one mutation of step b) to evaluate the effectiveness of said antiviral therapy.    
     
     
         9 . A method of evaluating the effectiveness of a nucleoside analogue as an antiviral therapy of an HIV-infected patient comprising: 
 (a) collecting a sample from an HIV-infected patient;    (b) determining whether the sample comprises a nucleic acid encoding a HIV reverse transcriptase having at least one mutation chosen from 62V, 75T, 77L, 116Y and 151M;    (c) using the presence of said at least one mutation of step b) to evaluate the effectiveness of said antiviral therapy.    
     
     
         10 . A method of evaluating the effectiveness of nevirapine as an antiviral therapy of an HIV-infected patient comprising: 
 (a) collecting a sample from an HIV-infected patient;    (b) determining whether the sample comprises a nucleic acid encoding a HIV reverse transcriptase having at least one mutation chosen from 101H, 101P, 103H, 103S, 103T, 106M, 181S, 190Q and 236L;    (c) using the presence of said at least one mutation of step b) to evaluate the effectiveness of said antiviral therapy.    
     
     
         11 . A method of evaluating the effectiveness of delavirdine as an antiviral therapy of an HIV-infected patient comprising: 
 (a) collecting a sample from an HIV-infected patient;    (b) determining whether the sample comprises a nucleic acid encoding a HIV reverse transcriptase having at least one mutation chosen from 101H, 101P, 103H, 103N, 103S, 103T, 106M, 181C, 181S, 190Q and 236L;    (c) using the presence of said at least one mutation of step b) to evaluate the effectiveness of said antiviral therapy.    
     
     
         12 . A method of evaluating the effectiveness of efavirenz as an antiviral therapy of an HIV-infected patient comprising: 
 (a) collecting a sample from an HIV-infected patient;    (b) determining whether the sample comprises a nucleic acid encoding a HIV reverse transcriptase having at least one mutation chosen from 101H, 101P, 103H, 103S, 103T, 106M, 181S, 190Q and 236L;    (c) using the presence of said at least one mutation of step b) to evaluate the effectiveness of said antiviral therapy.    
     
     
         13 . A method of evaluating the effectiveness of zidovudine as an antiviral therapy of an HIV-infected patient comprising: 
 (a) collecting a sample from an HIV-infected patient;    (b) determining whether the sample comprises a nucleic acid encoding a HIV reverse transcriptase having at least one mutation chosen from 184V, 41L and 215Y;    (c) using the presence of said at least one mutation of step b) to evaluate the effectiveness of said antiviral therapy.    
     
     
         14 . A method of evaluating the effectiveness of a protease inhibitor as an antiviral therapy of an HIV-infected patient comprising: 
 (a) collecting a sample from an HIV-infected patient;    (b) determining whether the sample comprises a nucleic acid encoding a HIV protease having at least one mutation chosen from 54L, 54M, 54V and any mutation at codon 84;    (c) using the presence of said at least one mutation of step b) to evaluate the effectiveness of said antiviral therapy.    
     
     
         15 . A method according to  claim 14  wherein the mutation at codon 84 is selected from 84A, 84C and 84L.  
     
     
         16 . A method according to  claim 14  or  15  wherein the at least one mutation in the HIV protease is combined with at least one mutation in the HIV protease at codon 10 and/or codon 90.  
     
     
         17 . A method according to any one of  claims 14  to  16  wherein the at least one mutation in the HIV protease is combined with at least one mutation in the HIV protease selected from 10I, 20R, 20T, 24I, 33F, 33I, 33L, 36I, 46L, 71T, 71V, 77I, 77V, 82I, 82V or 90M.  
     
     
         18 . A method of identifying a drug effective against drug resistant strains of HIV, comprising: 
 i) providing a HIV protease containing at least one mutation chosen from 54L, 54M, 54V or any mutation at codon 84;    ii) determining a phenotypic response of said drug to said HIV protease; and    iii) using said phenotypic response to determine the effectiveness of said drug.    
     
     
         19 . A drug identified using the method as claimed in  claim 18 .  
     
     
         20 . The method of  claim 18  wherein said phenotypic response is determined using a recombinant virus assay.  
     
     
         21 . A method of designing a therapy with d4T for treating a patient infected with HIV comprising: 
 (a) collecting a sample from an HIV-infected patient;    (b) determining whether the sample comprises a nucleic acid encoding a HIV reverse transcriptase having at least one mutation chosen from 44D, 77L, 115F, 118I, 184V, 208Y, 210W, 211K, 214F, 215F, 215Y, 219E, 219N, and 219Q;    (c) using the presence of said at least one mutation of step b) to design the antiviral therapy.    
     
     
         22 . A method of designing a therapy with lamivudine for treating a patient infected with HIV comprising: 
 (a) collecting a sample from an HIV-infected patient;    (b) determining whether the sample comprises a nucleic acid encoding a HIV reverse transcriptase having at least the mutation 184I;    (c) using the presence of said at least one mutation of step b) to design the antiviral therapy.    
     
     
         23 . A method of designing a therapy with abacavir for treating a patient infected with HIV comprising: 
 (a) collecting a sample from an HIV-infected patient;    (b) determining whether the sample comprises a nucleic acid encoding a HIV reverse transcriptase having at least one mutation chosen from 115F and 184V;    (c) using the presence of said at least one mutation of step b) to design the antiviral therapy.    
     
     
         24 . A method of designing a therapy with a nucleoside analogue for treating a patient infected with HIV comprising: 
 (a) collecting a sample from an HIV-infected patient;    (b) determining whether the sample comprises a nucleic acid encoding a HIV reverse transcriptase having at least one mutation chosen from 62V, 75T, 77L, 116Y and 151M;    (c) using the presence of said at least one mutation of step b) to design the antiviral therapy.    
     
     
         25 . A method of designing a therapy with nevirapine for treating a patient infected with HIV comprising: 
 (a) collecting a sample from an HIV-infected patient;    (b) determining whether the sample comprises a nucleic acid encoding a HIV reverse transcriptase having at least one mutation chosen from 101H, 101P, 103H, 103S, 103T, 106M, 181S, 190Q and 236L;    (c) using the presence of said at least one mutation of step b) to design the antiviral therapy.    
     
     
         26 . A method of designing a therapy with delavirdine for treating a patient infected with HIV comprising: 
 (a) collecting a sample from an HIV-infected patient;    (b) determining whether the sample comprises a nucleic acid encoding a HIV reverse transcriptase having at least one mutation chosen from 101H, 101P, 103H, 103N, 103S, 103T, 106M, 181C, 181S, 190Q and 236L;    (c) using the presence of said at least one mutation of step b) to design the antiviral therapy.    
     
     
         27 . A method of designing a therapy with efavirenz for treating a patient infected with HIV comprising: 
 (a) collecting a sample from an HIV-infected patient;    (b) determining whether the sample comprises a nucleic acid encoding a HIV reverse transcriptase having at least one mutation chosen from 101H, 101P, 103H, 103S, 103T, 106M, 181S, 190Q and 236L;    (c) using the presence of said at least one mutation of step b) to design the antiviral therapy.    
     
     
         28 . A method of designing a therapy with zidovudine for treating a patient infected with HIV comprising: 
 (a) collecting a sample from an HIV-infected patient;    (b) determining whether the sample comprises a nucleic acid encoding a HIV reverse transcriptase having at least one mutation chosen from 184V, 41L and 215Y;    (c) using the presence of said at least one mutation of step b) to design the antiviral therapy.    
     
     
         29 . A method of designing a therapy with a protease inhibitor for treating a patient infected with HIV comprising: 
 (a) collecting a sample from an HIV-infected patient;    (b) determining whether the sample comprises a nucleic acid encoding a HIV protease having at least one mutation chosen from 54L, 54M, 54V and any mutation at codon 84;    (c) using the presence of said at least one mutation of step b) to design the antiviral therapy.    
     
     
         30 . A method according to  claim 29  wherein the mutation at codon 84 is selected from 84A, 84C and 84L.  
     
     
         31 . A method according to  claim 29  or  30  wherein the at least one mutation in the HIV protease is combined with at least one mutation in the HIV protease at codon 10 and/or codon 90.  
     
     
         32 . A method according to any one of  claims 29  to  31  wherein the at least one mutation in the HIV protease is combined with at least one mutation in the HIV protease selected from 10I, 20R, 20T, 24I, 33F, 33I, 33L, 36I, 46L, 71T, 71V, 77I, 77V, 82I, 82V or 90M.