Sequence analysis of the HIV-1 protease coding region of 18 HIV-1-infected patients prior to HAART and possible implications on HAART.
BACKGROUND
The majority of HIV-infected patients are treated with highly active antiretroviral therapy (HAART) consisting of a combination of inhibitors of the protease (PIs) and the reverse transcriptase (RTIs). Analysis of mutations within these enzymes which are associated with development of resistance to the applied inhibitors is of major clinical importance. In particular, pre-existing mutations in previously untreated individuals may adversely influence the efficacy of HAART.


OBJECTIVE
The sequences of the protease coding regions of 18 HIV-1-infected patients were analysed prior to HAART.


METHODS
DNA was extracted from whole blood samples of HIV-1-infected treatment-naive patients. The protease coding region was amplified by nested PCR and sequenced directly. The resulting amino acid substitutions were analysed for known mutations associated with known resistance to PIs.


RESULTS
In all 18 analysed individuals we found 1-10 amino acid substitutions per patient in their HIV-1 protease coding region. These mutations occurred altogether at 27 positions of the 99 amino acids of the protease coding region. Seven of these mutated positions are associated with described resistance to PIs. Altogether, 15 of the 18 patients (83%) carried at least one such resistance-conferring alteration in their protease coding region. All patients are currently followed up during their present therapy to detect possible resistance formation to the applied PIs.


CONCLUSIONS
A large variety of pre-existing mutations associated with resistance to PIs was observed prior to their treatment. As none of the patients ever received HAART before and infection with resistant viral strains is very unlikely, these amino acid substitutions evidently reflect natural polymorphism of the HIV-1 protease coding region.
Gehringer
H
H
Department of Virology, Max von Pettenkofer--Institute, Munich, Germany.
Bogner
J R
JR
Goebel
F D
FD
Nitschko
H
H
von der Helm
K
K
D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D023241:Antiretroviral Therapy, Highly Active; D004252:DNA Mutational Analysis; D004279:DNA, Viral / Q000032:analysis; D004351:Drug Resistance; D015658:HIV Infections / Q000188:drug therapy*; D016333:HIV Protease / Q000187:drug effects / Q000235:genetics*; D017320:HIV Protease Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D006801:Humans; D008969:Molecular Sequence Data; D016133:Polymerase Chain Reaction; D011110:Polymorphism, Genetic
D004279:DNA, Viral; D017320:HIV Protease Inhibitors; D016333:HIV Protease