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

The genetic variation of the human immunodeficiency virus type 1 (HIV-1) pr otease gene (prt) permits the classification of HIV-1 strains into five dis tinct protease subtypes, which follow the gag subtyping patterns. The susce ptibilities of non-B-subtype strains to protease inhibitors (PIs) and other antiretroviral drugs remain largely unknown. Subtype F is the main non-B s train contributing to the Brazilian epidemic, accounting for 15 to 20% of t hese infections. In this work, we report the findings on 81 isolates from P I-naive Brazilian patients collected between 1993 and 1997. In addition, th e 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 tho se of both the Brazilian and the U.S. subtype B isolates. Analysis of the 8 1 Brazilian prt sequences demonstrated that the subtype F consensus sequenc e differs from the U.S. and Brazilian subtype B consensus in eight position s (I15V, E35D, M36I, R41K, R57K, Q61N, L63P, and L89M). The frequency of cr itical PI resistance substitutions (amino acid changes D30N, VS2A/F/T, I84V , N88D, and L90M) among Brazilian isolates is very low (mean, 2.5%), and th e associated secondary substitutions (amino acid positions 10L, 20K, 36M, 3 6M, 48G, 54I 63P, 71A, and 77A) are infrequent. These observations document the relative rarity of resistance to PIs in the treatment of patients infe cted crith HIV-1 subtype F in South America.