Impact of frequent natural polymorphisms at the protease gene on the in vitro susceptibility to protease inhibitors in HIV-1 non-B subtypes.
BACKGROUND
Naturally-occurring polymorphisms at the human immunodeficiency virus type 1 (HIV-1) protease which have been associated to resistance to protease inhibitors (PIs) in clade B viruses are frequently found in non-B subtypes, with unknown clinical significance.


OBJECTIVE
To assess the susceptibility of non-B viruses to different PIs.


METHODS
Plasma samples from 58 drug-naive individuals infected with HIV-1 non-B subtypes (2A, 22C, 2D, 1F, 29G and 2J) defined by phylogenetic analyses of the protease gene were tested using a phenotypic assay (PhenoSense, ViroLogic, South San Francisco, CA, USA). Twenty of them were further analyzed with another assay (Antivirogram, Virco, Mechelen, Belgium). All 58 non-B viruses harbored amino acid substitutions associated with reduced PI susceptibility in clade B (positions 10, 20, 36, 63, 70, 77 and 82).


RESULTS
Using PhenoSense-HIV assay, all but two individuals harbored viruses completely susceptible to all six PIs tested (indinavir (IDV), ritonavir (RTV), saquinavir (SQV), nelfinavir (NFV), amprenavir (APV), lopinavir (LPV)). The two viruses with reduced susceptibility belonged to clade G. The first virus, which had K20I, M36I and V82I, showed 2.9-fold decreased susceptibility to APV, while the second virus showed 3.9-fold decreased susceptibility to both NFV and RTV, with amino acid substitutions K20I, M36I, L63P and V82I. Of note, several other viruses displayed the same constellation of mutations but without showing any reduced susceptibility, suggesting that these polymorphisms per se do not affect PI susceptibility.


CONCLUSIONS
PI susceptibility in HIV-1 non-B viruses seems to be preserved despite the presence of polymorphic changes which have been associated to PI resistance in clade B viruses.
Service of Infectious Diseases, Hospital Carlos III, Madrid, Spain.
Africa
A
Holguín
Ellen
E
Paxinos
Kurt
K
Hertogs
Chad
C
Womac
Vincent
V
Soriano
D024882:Drug Resistance, Viral; D016333:HIV Protease / Q000235:genetics*; D017320:HIV Protease Inhibitors / Q000494:pharmacology*; D015497:HIV-1 / Q000145:classification / Q000187:drug effects* / Q000201:enzymology* / Q000235:genetics; D006801:Humans; D008297:Male; D008826:Microbial Sensitivity Tests; D008969:Molecular Sequence Data; D009154:Mutation; D010641:Phenotype; D011110:Polymorphism, Genetic; D011933:Reagent Kits, Diagnostic; D017422:Sequence Analysis, DNA
D017320:HIV Protease Inhibitors; D011933:Reagent Kits, Diagnostic; D016333:HIV Protease