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. 1999 Feb;43(2):253-8.
doi: 10.1128/AAC.43.2.253.

Genetic variation and susceptibilities to protease inhibitors among subtype B and F isolates in Brazil

Affiliations

Genetic variation and susceptibilities to protease inhibitors among subtype B and F isolates in Brazil

A Tanuri et al. Antimicrob Agents Chemother. 1999 Feb.

Abstract

The genetic variation of the human immunodeficiency virus type 1 (HIV-1) protease gene (prt) permits the classification of HIV-1 strains into five distinct protease subtypes, which follow the gag subtyping patterns. The susceptibilities of non-B-subtype strains to protease inhibitors (PIs) and other antiretroviral drugs remain largely unknown. Subtype F is the main non-B strain contributing to the Brazilian epidemic, accounting for 15 to 20% of these infections. In this work, we report the findings on 81 isolates from PI-naive Brazilian patients collected between 1993 and 1997. In addition, the relevant PI resistance mutations and their phenotypes were determined in vitro for 15 of these patients (B = 9 and F = 6). Among these, the subtype F samples evidenced high sensitivities in vitro to ritonavir and indinavir, with MICs at which 50 and 90% of the isolates are inhibited similar to those of both the Brazilian and the U.S. subtype B isolates. Analysis of the 81 Brazilian prt sequences demonstrated that the subtype F consensus sequence differs from the U.S. and Brazilian subtype B consensus in eight positions (I15V, E35D, M36I, R41K, R57K, Q61N, L63P, and L89M). The frequency of critical PI resistance substitutions (amino acid changes D30N, V82A/F/T, I84V, N88D, and L90M) among Brazilian isolates is very low (mean, 2.5%), and the associated secondary substitutions (amino acid positions 10L, 20K, 36M, 46M, 48G, 54I, 63P, 71A, and 77A) are infrequent. These observations document the relative rarity of resistance to PIs in the treatment of patients infected with HIV-1 subtype F in South America.

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Figures

FIG. 1
FIG. 1
Phylogenetic classification. The distinct HIV-1 subtypes are delineated, and the tree was generated by the neighbor-joining method (for details, see Materials and Methods). The scale bar shows the ratio of nucleotide substitutions for a given horizontal branch length. Vertical distances are for clarity only. The bootstrap values (mean of 100 reiterations) of all major branches of the tree are shown. The following reference sequences were included, corresponding to the subtype shown in parentheses: CHIU455 and CH1MAL (A); CH1MN, CH1NY5, CH1YOL, CH1BRU, CH1RF, and CH1SF2 (B); CSP586 and CBr19C (C); CH1ELI and CHZ2Z6 (D); and C7944 and Br22f (F). The SIVCPZ protease sequence was used as an outgroup to root the tree.
FIG. 2
FIG. 2
Amino acid alignment of Brazilian protease sequences: The U.S. consensus prt sequence (17) is provided for comparison (upper sequence), and Brazilian sequences are aligned beneath. The Brazilian sequences are segregated into subtypes B (upper) and F (lower). The protease functional domains (active site, flap region, and psi loop) are shown at the top of the consensus sequence. The five amino acid positions critical for PI drug resistance (amino acid positions 30D, 82V, 84I, 88N, and 90L) are depicted in boldface italics, and the secondary positions (amino acid positions 10L, 20K, 36M, 46M, 48G, 54I, 63P, 71A, and 77A) are marked in boldface only. The molecular signature sites that differentiate subtype B from subtype F are designated with asterisks.

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