Ays are ob-November 24,EUROPEAN JOURNAL OF MEDICAL RESEARCHserved at a very
Ays are ob-November 24,EUROPEAN JOURNAL OF MEDICAL RESEARCHserved at a very early stage with no trace of N155H having been selected beforehand, suggesting that in these viruses, Q148R/H/K or Y143R/C could constitute a preferable early pathway for initial viral breach during RAL treatment.The dynamics of HIV evolution under pharmacological pressure by RAL in vivo are largely explained by the phenotypic properties of the different IN mutants involved in this evolution, both in PubMed ID:https://www.ncbi.nlm.nih.gov/pubmed/29069523 terms of resistance (fold-change in IC50) and in terms of replicative capacity (RC). Most studies have focused on the effect of primary and secondary mutations of the N155H and Q148R/H/K pathways, leaving aside the Y143R/C pathway, for which little information is available. Phenotypic analysis of viral clones carrying the N155H mutation have found that it mediated significant but moderate levels of resistance to RAL. Introduction of N155H in a wild-type HIV-1 subtype B reference molecular clone such as HIV-1 IIIB or pNL4-3 produced a change in RAL IC50 of 16- to 32-fold, at the expense of minimal (30 -40 ) loss of replicative capacity. Mutations at codon 148 appeared to produce stronger changes in RAL IC50 (18- to 78-fold, depending on the substitution and on the experimental system), together with a more prominent loss (40 -70 ) of RC. Thus, N155H produces less resistance than Q148R/H/K, but had a milder impact on viral RC. When examined using the “selective advantage profile” system, which incorporates drug susceptibility and RC in a single assay expressing the selective advantage of a mutant virus relative to wild-type as a function of drug concentration [34, 42, 44], N155H had clearly a strong positive advantage over a wide range of RAL concentration, as opposed to Q148H [44], which only expressed minimal selective advantage over wild-type across a markedly narrower range of RAL concentration (Fig. 4). Addition of secondary mutations both to N155H and to Q148R/H/K mutations dramatically increased RAL resistance and significantly improved RC [10, 17, 40, 44]. The association of either of the Q148 mutations with secondary G140S, G140A or E138K could produce fold-changes in IC50 that were above the maximal 150-fold resistance rate AG-490 chemical information measurable in the Monogram assay in Fransen et al. [17], but this effect was only seen with specific pairs of Q148 and G140 substitutions. For example, secondary mutation G140S was found to exert maximal effect only when associated with Q148H or Q148R, but its association with Q148K reduced resistance from a 48-fold change in IC50 to PubMed ID:https://www.ncbi.nlm.nih.gov/pubmed/25447644 a 6 fold-change, an effect that appears to be independent of viral RC [17]. Consistent with these findings, Quercia et al. reported that G140S produced a change in RAL IC50 of 1436-fold [44]. The addition of secondary mutation E92Q also markedly increased the level of resistance conferred by mutation N155H with E92Q : viruses with both mutations expressed changes in RAL IC50 of >150-fold in Fransen et al. and of 492-fold in Quercia et al [17, 44]. When analysed using the selective advantage profile method, the combination of Q148H and G140S was found to express a level of advantage that was higher and wider than any of the other dual mutations tested. In addition to their effect on resistance, the association ofPHENOTYPIC PROPERTIES OF RAL RESISTANCE MUTATIONSG140 mutations with Q148R/H/K mutations also helps improving viral RC. For example, in Fransen et al., addition of G140S to Q148H increased RC from 43.
