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Antimicrobial Agents and Chemotherapy, September 2003, p. 2817-2822, Vol. 47, No. 9
0066-4804/03/$08.00+0     DOI: 10.1128/AAC.47.9.2817-2822.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

In Vitro Hypersusceptibility of Human Immunodeficiency Virus Type 1 Subtype C Protease to Lopinavir

Luis M. F. Gonzalez,1 Rodrigo M. Brindeiro,1 Michelle Tarin,2 Alexandre Calazans,1 Marcelo A. Soares,1 Sharon Cassol,1 and Amilcar Tanuri1*

Laboratório de Virologia Molecular, Departamento de Genética, Universidade Federal do Rio de Janeiro, CCS, Bloco A, Cidade Universitária, Ilha do Fundão, 21944-970 Rio de Janeiro, RJ, Brazil,1 HIV-1 Molecular Virology and Bionformatics Unit, Africa Center/Nelson Mandela School of Medicine, University of Natal, Durban, South Africa2

Received 10 March 2003/ Returned for modification 12 May 2003/ Accepted 16 June 2003

In order to characterize the impact of genetic polymorphisms on the susceptibility of subtype C strains of human immunodeficiency virus type 1 to protease inhibitors (PIs), a subtype B protease that originated from an infectious clone was modified through site-directed mutagenesis to include the amino acid residue signatures of subtype C viruses (I15V, M36I, R41K, H69K, L89 M) with (clone C6) or without (clone C5) an I93L polymorphism present as a molecular signature of the worldwide subtype C protease. Their susceptibilities to commercially available PIs were measured by a recombinant virus phenotyping assay. We could not detect any differences in the 50% inhibitory concentration (IC50s) of amprenavir, indinavir, ritonavir, saquinavir, and nelfinavir for the clones analyzed. However, we did observe hypersusceptibility to lopinavir solely in clone C6, which includes the I93L substitution (a 2.6-fold decrease in the IC50 compared to that for the subtype B reference strain). The same phenotypic behavior was observed for 11 Brazilian and South African clinical isolates tested, in which only subtype C isolates carrying the I93L mutation presented significant hypersusceptibility to lopinavir.

* Corresponding author. Mailing address: Laboratório de Virologia Molecular, Departamento de Genética, Universidade Federal do Rio de Janeiro, CCS, Bloco A, Cidade Universitária, Ilha do Fundão, 21944-970 Rio de Janeiro, RJ, Brazil. Phone: 5521 5626384. Fax: 5521 25626355. E-mail: atanuri{at}biologia.ufrj.br.

Antimicrobial Agents and Chemotherapy, September 2003, p. 2817-2822, Vol. 47, No. 9
0066-4804/03/$08.00+0     DOI: 10.1128/AAC.47.9.2817-2822.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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