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Amprenavir-resistant HIV-1 exhibits lopinavir cross-resistance and reduced replication capacity

Prado, Julia G.a; Wrin, Terrib; Beauchaine, Jeffb; Ruiz, Lidiaa; Petropoulos, Christos J.b; Frost, Simon D. W.c; Clotet, Bonaventuraa; D'Aquila, Richard T.d; Martinez-Picado, Javiera

Clinical Science

Objectives: To evaluate protease inhibitor (PI) cross-resistance and reductions in replication capacity conferred by amprenavir-selected mutations.

Methods: HIV-1IIIB variants derived from passage in increasing concentrations of amprenavir were studied, as well as 3′Gag/protease recombinants derived from them. These strains progressively accumulated mutations at codons 10, 46, 47, 50 and 84 in the protease as well as a p1/p6 cleavage site mutation at codon 449 in Gag. Their susceptibility (IC50) to various PI and their corresponding replication capacities were evaluated by a single-cycle growth assay and compared with measures using competitive cultures and p24 antigen production.

Results: Amprenavir susceptibility decreased with increasing numbers of protease mutations. Changes in lopinavir susceptibility paralleled changes in amprenavir susceptibility. Certain amprenavir-selected mutants conferred greater than 10-fold cross-resistance to lopinavir, including PrL10F/M46I/I50V-GagL449F (19-fold) and PrL10F/M46I/I47V/I50V-GagL449F (31-fold). Moreover, one isolate with only two mutations in the protease (L10F/84V) and GagL449F displayed a 7.7-fold increase in lopinavir IC50. Low-level cross-resistance to ritonavir and nelfinavir was also observed. The replication capacity of viruses containing either I84V or I50V was at least 90% lower than the reference virus in the single-cycle assay. The order of relative replication capacity was wild-type > L10F > L10F/I84V > L10F/M46I/I50V > L10F/M46I/I47V/I50V.

Conclusion: These results indicate that until more comprehensive genotype–phenotype correlations between amprenavir and lopinavir susceptibility are established, phenotypic testing may be preferable to genotyping to detect cross-resistance, and should be considered when switching patients from a failing amprenavir-containing regimen. This study also provides data on the concordance of replication capacity measurements generated using rapid single-cycle growth and competition assays.

From the aIrsiCaixa Foundation, Hospital Germans Trias i Pujol, Universitat Autònoma de Barcelona, Badalona, Spain; bViroLogic, Inc., South San Francisco, CA, USA; cDepartment of Pathology, University of California, San Diego, USA; and dVanderbilt University Medical Center, Nashville, TN, USA.

Correspondence to: Dr Javier Martinez-Picado, IrsiCaixa Foundation, Hospital Germans Trias i Pujol, Ctra. de Canyet s/n, 08916 Badalona, Spain. Tel: +34 93 4656374; fax: +34 93 4653968; e-mail: javiermp@ns.hugtip.scs.es

Received: 16 August 2001;

revised: 30 November 2001; accepted: 6 December 2001.

Sponsorship: This study was supported in part by grants FIS 01/1122, FIPSE 36177/01 and R01 AI29193. J.G.P. was supported by grant BEFI 01/9067. J.M.-P. was supported by contract FIS 99/3132 from the Fundacio per a la Recerca Biomedica Germans Trias i Pujol, in collaboration with the Spanish Health Department. S.D.W.F. was supported by the National Institutes of Health (grant no. AI47745).

© 2002 Lippincott Williams & Wilkins, Inc.