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1 June 2005

Volume 191, Number 11
The Journal of Infectious Diseases 2005;191:1961–1970
© 2005 by the Infectious Diseases Society of America. All rights reserved.
0022-1899/2005/19111-0024$15.00
DOI: 10.1086/430002
MAJOR ARTICLE

Low Accumulation of L90M in Protease from Subtype F HIV‐1 with Resistance to Protease Inhibitors Is Caused by the L89M Polymorphism

Alexandre Calazans,1

Rodrigo Brindeiro,1

Patrícia Brindeiro,1

Hugo Verli,3

Mônica B. Arruda,1

Luis Manuel Felipe Gonzalez,1

Jorge A. Guimarães,3

Ricardo Sobhie Diaz,4

Octavio A. C. Antunes,2 and

Amilcar Tanuri1

1Department of Genetics, Biology Institute, and 2Department of Inorganic Chemistry, Chemistry Institute, Federal University of Rio de Janeiro, Rio de Janeiro, 3Center of Biotechnology, Federal University of Rio Grande do Sul, Porto Alegre, and 4Retrovirology Laboratory, Federal University of São Paulo, São Paulo, Brazil

Background.This work evaluates the role of subtype F human immunodeficiency virus type 1 (HIV‐1) protease (PR) substitutions L89M and L90M in viral replication and resistance to PR inhibitors (PIs).

Methods.Subtype B and F PR genes were subjected to site‐directed mutagenesis, to create and reverse the methionine at positions 89 and 90. Viruses were re‐created in cell culture, and their replicative capacity was assessed by fitness assay. Generated viruses were also phenotyped for PI resistance.

Results.The subtype F clone (89M90L) showed a replicative capacity comparable to that of the PI‐susceptible subtype B clone (89L90L) and was more fit than the L89M mutated subtype B clone (89M90L). Both 89M90M subtype B and F clones presented the lowest fitness s values. The L89M mutation impacted phenotypic resistance to all PIs in half of the subtype F isolates but not in the subtype B isolates. Subtype F isolates presented a phenotypic profile similar to that of subtype B isolates when the M89L mutation was introduced.

Conclusion.The L89M mutation in subtype F viruses is a high genetic barrier to the accumulation of the L90M resistance mutation and can function as a resistance mutation, depending on the presence of other polymorphisms in the subtype F PR backbone.

Received 21 May 2004; accepted 10 December 2004; electronically published 28 April 2005.

Reprints or correspondence: Dr. Amilcar Tanuri, 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 ().

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  • Financial support: Brazilian Program of STD/AIDS; Coordenação de Aperfeiçoamento de Pessoal de Ensino Superior.

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