Distinct resistance mutation and polymorphism acquisition in HIV-1 protease of subtypes B and F1 from children and adult patients under virological failure

Abstract

The goal of this work was to compare the differences between human immunodeficiency virus type 1 (HIV-1) of B and F1 subtypes in the acquisition of major and minor protease inhibitor (PI)-associated resistance mutations and of other polymorphisms at the protease (PR) gene, through a cross sectional study. PR sequences from subtypes B and F1 isolates matched according to PI exposure time from Brazilian patients were included in this study. Sequences were separated in four groups: 24 and 90 from children and 141 and 99 from adults infected with isolates of subtypes F1 and B, respectively. For comparison, 211 subtype B and 79 subtype F1 PR sequences from drug-naïve individuals were included. Demographic and clinical data were similar among B- and F1-infected patients. In untreated patients, mutations L10V, K20R, and M36I were more frequent in subtype F1, while L63P, A71T, and V77I were more prevalent in subtype B. In treated patients, K20M, D30N, G73S, I84V, and L90M, were more prevalent in subtype B, and K20T and N88S were more prevalent in subtype F1. A higher proportion of subtype F1 than of subtype B strains containing other polymorphisms was observed. V82L mutation was present with increased frequency in isolates from children compared to isolates from adults infected with both subtypes. We could observe a faster resistance emergence in children than in adults, during treatment with protease inhibitors. This data provided evidence that, although rates of overall drug resistance do not differ between subtypes B and F1, the former accumulates resistance at higher proportion in specific amino acid positions of protease when compared to the latter.

Fig. 1

HIV-1 subtype B and F1 viruses with at least one major or minor resistance mutation. Different PI treatment exposure periods (in months) were plotted for each subtype and for each mutation class. (A) Comparison between subtype B isolated from infected adults and children; (B) comparison between subtypes B and F1 isolated from infected adults. Black double arrows denote significance in the difference of proportions between subtypes B isolated from children and adults at the 0.05 p-value level. The exposure time point 0 means the proportion of mutant strains isolated from untreated individuals. Numbers in parentheses above exposure time periods denote the number of sequences from children and adults (in panel A) and from subtypes B and F1 (in panel B), respectively.