|
|
| Impact on Fitness Conferred by Amprenavir (APV) Resistance Mutations |
W. HARRIS, S. RANDALL, V. MANOHITHARAJAH, F. XU, R. ELSTON, M. TISDALE, W. SNOWDEN;
GlaxoSmithKline, Stevenage, United Kingdom. |
| Presentation Number: 1766 |
| Background APV resistance generated during unboosted APV therapy (without low-dose ritonavir) developsthrough four distinct genetic pathways characterised by the presence of key mutations I50V, I54L/M, V32I+I47V or I84V which confer different levels of APV resistance (~10, 4, 5 and 8-fold respectively in clinical isolates also containing accessory mutations). Selection of a specific pathway correlates with APV trough levels; the I50V mutation confers the greatest reduction in susceptibility and occurs at the highest Cmin, whereas I54L/M confers the least resistance and occurs at low Cmin. The impact of these mutations on viral fitness may differ and those with greater impact may only be selected when necessary i.e. according to the level of resistance required to overcome the prevailing plasma concentration. Methods A panel of viruses (n=20) containing key APV mutations, either alone or in combination with the most prevalent accessory mutations observed in clinical isolates (L10I, L33F, M46I/L) were assessed for impact on viral fitness, by measurement of p24 release and infectivity. Results A hierarchy of fitness was detected : e.g. at day 4: WT(100%)>I54M (74%) >I54L (64%)>V32I (38%)>I84V (10%)>I50V (1%). Accessory mutations partially restore fitness in some cases e.g. WT>V32I+I47V>V32I. With I50V, the addition of accessory mutations leaves a virus which is still less fit than virus with the other key mutations, and significantly less fit than wild-type:WT>> V32I> I50V+M46I> I50V+L33F=I84V>> I50V. Clonal analysis of clinical isolates also confirmed that accessory mutations are needed for stable detection of APV resistance pathways. Conclusion The selection of a specific APV-resistance genotype is a balance between viral fitness and level of resistance required to overcome prevailing drug level. The APV-specific I50V confers the greatest impact on susceptibility and fitness. |
| |
|
|
|
|
|
|
|
|
The Online Abstract Submission and Invitation System
© 1996 - 2010 Coe-Truman Technologies, Inc. All rights reserved.
|
|
|
|
|
|
