The fitness cost of mutations associated with human immunodeficiency virus type 1 drug resistance is modulated by mutational interactions

Abstract

It is generally accepted that the fitness cost of resistance mutations plays a role in the persistence of transmitted drug-resistant human immunodeficiency virus type 1 and that mutations that confer a high fitness cost are less able to persist in the absence of drug pressure. Here, we show that the fitness cost of reverse transcriptase (RT) mutations can vary within a 72-fold range. We also demonstrate that the fitness cost of M184V and K70R can be decreased or enhanced by other resistance mutations such as D67N and K219Q. We conclude that the persistence of transmitted RT mutants might range widely on the basis of fitness and that the modulation of fitness cost by mutational interactions will be a critical determinant of persistence.

FIG. 1.

Competition dynamics between HXB2_wt and HXB2_K103N or HXB2_K65R. Experiments were initiated at a 50:50 (A and B) or a 75:25 (C and D) mutant-to-wild-type ratio. Panels A through D show the changes in the relative proportion of the two competing variants over time measured in a single competition experiment. Panels E and F show the average fitness vector obtained for K103N and K65R, respectively. To calculate the fitness vector, the proportion of the mutant with respect to the wild-type (WT) virus (Rn) was divided by its ratio in the initial mixture (Ro), and this value (Rn/Ro) was plotted versus the competition passage. Bars denote the standard errors of the means.

FIG. 2.

Absolute fitness differences between HXB2_wt and drug-resistant mutants. Results obtained from duplicate experiments (K70R, K103N, M184V, and K65R) or single determinations are shown. Error bars indicate the standard errors of the best-fit values obtained from the fitness vectors. All mutations, with the exception of L210W, showed a fitness cost as indicated by a negative slope in the fitness vector. The absolute fitness differences (n-fold) (95% confidence interval) were 0.4 ± 0.2 (0.4 to 1.2) for L210W, 0.4 ± 0.2 (0.1 to 1) for K70R, 0.6 ± 0.4 (0.4 to 1.5) for Y181C, 1.4 ± 0.3 (0.8 to 2) for K219Q, 2 ± 0.1 (1.6 to 2.5) for L74V, 3.7 ± 0.2 (2.6 to 4.9) for D67N, 4.5 ± 0.7 (2.8 to 6.2) for M41L, 6.2 ± 0.2 (5.7 to 6.6) for K103N, 12.9 ± 1 (10 to 15.8) for T215Y, 14 ± 0.7 (12 to 15.8) for M184V, and 29 ± 0.5 (29 to 37) for K65R.

FIG. 3.

Modulation of the fitness cost of M184V, K70R, or T215Y/F by other drug resistance mutations. Panels A, B, and C show the fitness plots of different HXB2 mutants carrying M184V, K70R, or T215Y/F alone or in association with other mutations. Panel D shows the fitness vectors obtained in patient-derived viruses carrying the M184V mutation alone (isolate RD160) or in combination with K103N (isolate RD110), K70R (isolate RD583), or M41L/T215Y (isolate RD879). Results obtained from duplicate experiments (A, B, and D) or single determinations (C) are shown. Bars denote the standard errors of the means. WT, wild type.