Journal of Antimicrobial Chemotherapy, Vol 39, 771-779, Copyright © 1997 by The British Society for Antimicrobial Chemotherapy
KJ Ives, H Jacobsen, SA Galpin, MM Garaev, L Dorrell, J Mous, K Bragman and JN Weber
We examined the phenotypic and genotypic properties of virus from the
peripheral blood mononuclear cells (PBMC) and plasma of eight HIV-1-
infected asymptomatic patients before and during monotherapy with the
proteinase inhibitor saquinavir. Susceptibility of primary isolates to drug
was assessed in PBMC culture by deriving IC50 and IC90 values. The observed
increases in IC50 and IC90 after approximately one year of therapy with a
dosage of 600 mg tds suggests the presence of virus resistant to saquinavir
in vivo. The magnitude of this altered susceptibility ranged from
three-fold to in one case 100-fold. In two patients a greater than
eight-fold decrease in susceptibility to saquinavir was observed.
Sequencing of the proteinase genes in viral RNA obtained from patient
plasma and/or PBMC was carried out by PCR in parallel with sensitivity
testing. In each case between nine and 12 clones were analysed. In the two
patients from whom virus had greater than eight-fold reduction in
susceptibility, a point mutation was observed in the viral proteinase
(Leu90--> Met/Ile). Further mutations were observed at residues 36, 71
and 84 in these subjects. In a third patient, in whom an eight-fold
increase in HIV IC50 of saquinavir was observed, no mutations were detected
in the proteinase; sequencing of proteinase cleavage sites in viral gag-pol
revealed no significant mutations. In no patient was a Gly48-->Val
mutation observed, although this has been associated with resistance in
vitro. The Leu90-->Met mutation was observed in five subjects, but a
greater than eight-fold phenotypic change in antiviral susceptibility was
seen in only two of these. Hence, in vivo, the Leu90-->Met but not the
Gly48-->Val mutation is necessary, but not sufficient, for phenotypic
resistance to saquinavir in HIV.
JOURNAL ARTICLE
Emergence of resistant variants of HIV in vivo during monotherapy with the proteinase inhibitor saquinavir
Department of GU Medicine & Communicable Diseases, Imperial College School of Medicine at St Mary's, London, UK.
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