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Journal of Virology, January 1999, p. 850-854, Vol. 73, No. 1
0022-538X/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.
Constrained Evolution of Human Immunodeficiency
Virus Type 1 Protease during Sequential Therapy with Two Distinct
Protease Inhibitors
Anne
Dulioust,1
Sylvie
Paulous,2,3
Laurent
Guillemot,4
Anne-Marie
Delavalle,1
François
Boué,1 and
François
Clavel2,3,*
Service de Médecine Interne,
Hôpital Antoine Béclère,
Clamart,1
Laboratoire de Recherche
Antivirale, IMEA-INSERM, Hôpital Bichat,2
Unité d'Oncologie Virale,3 and
Centre de Biologie Médicale Spécialisée,
Institut Pasteur,4 Paris, France
Received 27 July 1998/Accepted 15 October 1998
Human immunodeficiency virus type 1 (HIV-1) variants that have
developed protease (PR) inhibitor resistance most often display cross-resistance to several molecules within this class of
antiretroviral agents. The clinical benefit of the switch to a second
PR inhibitor in the presence of such resistant viruses may be
questionable. We have examined the evolution of HIV-1 PR genotypes and
phenotypes in individuals having failed sequential treatment with two
distinct PR inhibitors: saquinavir (SQV) followed by indinavir (IDV).
In viruses where typical SQV resistance mutations were detected before the change to IDV, the corresponding mutations were maintained under
IDV, while few additional mutations emerged. In viruses where no SQV
resistance mutations were detected before the switch to IDV, typical
SQV resistance profiles emerged following the introduction of IDV. We
conclude that following suboptimal exposure to a first PR inhibitor,
the introduction of a second molecule of this class can lead to rapid
selection of cross-resistant virus variants that may not be detectable
by current genotyping methods at the time of the inhibitor switch.
Viruses committed to resistance to the first inhibitor appear to bear
the "imprint" of this initial selection and can further adapt to
the selective pressure exerted by the second inhibitor following a
pathway that preserves most of the initially selected mutations.
*
Corresponding author. Mailing address: Laboratoire de
Recherche Antivirale, IMEA-INSERM, Hôpital Bichat-Claude Bernard,
46, rue Henri Huchard, 75018 Paris, France. Phone: 33 1 40 25 63 63. Fax: 33 1 40 25 87 80. E-mail: clavel{at}bichat.inserm.fr.
Journal of Virology, January 1999, p. 850-854, Vol. 73, No. 1
0022-538X/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.
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