HIV protease genotype and viral sensitivity to HIV protease inhibitors following saquinavir therapy.
OBJECTIVE
To examine the relationship between HIV protease genotype and altered protease inhibitor sensitivity of isolates from patients after therapy with saquinavir (SQV) in its hard gelatin formulation.


METHODS
Forty-one post-therapy isolates and corresponding baseline samples were obtained from 37 patients in four different clinical trials after therapy with SQV for 16-147 weeks. Post-therapy isolates were selected on the basis of preliminary sequence or drug sensitivity data.


RESULTS
Fifteen out of 17 isolates without detectable Val-48 or Met-90 mutations retained sensitivity to SQV. (The remaining isolates showed only a marginal increase in median inhibitory concentration.) In addition, three out of 15 isolates with Met-90 retained sensitivity to all other protease inhibitors tested (indinavir, ritonavir, amprenavir, nelfinavir). Of the isolates showing reduced sensitivity to SQV, six out of 22 retained sensitivity to all other protease inhibitors, whereas only four out of 22 showed broad cross-resistance to all protease inhibitors tested. The reduction in sensitivity correlated closely with the presence of Val-48 or Met-90. Subsequent accessory substitutions were also linked to reduced sensitivity. However, significant linkage was observed only between mutations at residues 48 and 82 and between those at residues 82 and 74.


CONCLUSIONS
Recruitment of Val-48/Met-90 mutations was not found to be synonymous with cross-resistance. Indeed, the majority of isolates with these mutations retained sensitivity to at least one protease inhibitor (Val-48, 86%; Met-90, 77%). The recruitment of accessory mutations may occur only after the selection of key resistance mutations. Furthermore, Met-90 was found to be a poor marker of cross-resistance in SQV-treated patients.
Roche Discovery Welwyn, Welwyn Garden City, Herts, UK.
C
C
Craig
E
E
Race
J
J
Sheldon
L
L
Whittaker
S
S
Gilbert
A
A
Moffatt
J
J
Rose
S
S
Dissanayeke
G W
GW
Chirn
I B
IB
Duncan
N
N
Cammack
D019943:Amino Acid Substitution; D002219:Carbamates; D002986:Clinical Trials as Topic; D004279:DNA, Viral / Q000737:chemistry; D016208:Databases, Factual; D005663:Furans; D008040:Genetic Linkage; D005838:Genotype; D015658:HIV Infections / Q000188:drug therapy*; D016333:HIV Protease / Q000187:drug effects / Q000235:genetics*; D017320:HIV Protease Inhibitors / Q000627:therapeutic use*; D006801:Humans; D019469:Indinavir / Q000627:therapeutic use; D008715:Methionine / Q000032:analysis; D019888:Nelfinavir / Q000627:therapeutic use; D010641:Phenotype; D016133:Polymerase Chain Reaction; D019438:Ritonavir / Q000627:therapeutic use; D019258:Saquinavir / Q000627:therapeutic use*; D013449:Sulfonamides / Q000627:therapeutic use; D014633:Valine / Q000032:analysis
D002219:Carbamates; D004279:DNA, Viral; D005663:Furans; D017320:HIV Protease Inhibitors; D013449:Sulfonamides; C095108:amprenavir; D019469:Indinavir; D008715:Methionine; D016333:HIV Protease; D014633:Valine; D019888:Nelfinavir; D019258:Saquinavir; D019438:Ritonavir