Effect of HIV/HCV Co-Infection on the Protease Evolution of HIV-1B: A Pilot Study in a Pediatric Population

Abstract

This pilot study evaluates in pediatric patients the impact of HIV/HCV coinfection in the molecular evolution of the HIV-1 subtype B protease (HIV-1BPR). For this study, HIV-1B/HCV coinfected (15) and HIV-1B monoinfected (56) patients with available HIV-1B pol sequences were enrolled. Both groups of patients had comparable gender frequencies and average age, time of infection, antiretroviral treatment (ART) exposure and time under ART. Prevalence of drug resistance mutations (DRM), genetic diversity, number of synonymous (d_S) and non-synonymous (d_N) mutations per site and selection pressures (d_N - d_S) in the HIV-1BPR were estimated and compared between mono- and coinfected patients. Both HIV-1B populations presented similar genetic diversity (0.050 ± 0.02 vs. 0.045 ± 0.01) and d_S (0.074 ± 0.03 vs. 0.078 ± 0.04). In turn, in coinfected patients the HIV-1BPR had higher d_N (0.045 ± 0.01 vs. 0.024 ± 0.01) and d_N-d_S (-0.026 ± 0.02 vs. -0.048 ± 0.04) values, and less amino acid sites under purifying selection (4.2% vs. 42.1%) than in monoinfected patients. Accordingly, in co-infection with HCV, the HIV-1BPR sites 50, 53, 82, 84 and 88 - associated with resistance to PIs - were under neutral evolution, whereas these sites were under purifying selection in monoinfected patients. This pilot study suggests that HIV-1B may evolve differently in the presence than in the absence of HCV.

Figure 1

Genetic distances in monoinfected (grey) and coinfected (green) HIV-1BPR sequences. Panel A, Mean genetic distances of HIV-1BPR in coinfected (n = 11) and monoinfected (n = 41) pediatric treated patients. Panel B, Mean genetic distances of HIV-1B PR from both groups of patients according to date of birth period; P1: 1984-1992 (HIV/HCV n = 5, HIV n = 22); P2: 1993-2001 (HIV/HCV n = 6, HIV n = 22). Panel C, mean genetic distances according to time under ART considering around five years under ART. NS, not significant; *significant. Three outliers sequences from the coinfected group and seven from the monoinfected group were removed to avoid estimation biases.

Figure 2

Selection pressures (d_N − d_S) in the HIV-1BPR of coinfected and monoinfected patients. Selection pressures were estimated from HIV-1B PR sequences of 11 coinfected and 41 monoinfected treated children. Asterisks indicate significant differences between mono- and coinfected patients.

Figure 3

Selection pressures in the HIV-1BPR sites associated with major PI resistance in mono- and coinfected children. Red squares denote sites under purifying or negative selection, and blue squares denote sites under neutral evolution. PI, protease inhibitors; aa, amino acid site.