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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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