JAC Advance Access originally published online on February 16, 2009
Journal of Antimicrobial Chemotherapy 2009 63(4):795-804; doi:10.1093/jac/dkp014
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Original research |
Quasispecies variant dynamics during emergence of resistance to raltegravir in HIV-1-infected patients
1 UPMC Univ Paris 06, F-75005 Paris, France 2 Laboratoire de Virologie, AP-HP, Hôpital Pitié-Salpêtrière, F-75013 Paris, France 3 LBPA, CNRS, Ecole Normale Supérieure de Cachan, Cachan, France 4 Service de Médecine Interne, Centre Hospitalier de Royan, Royan, France 5 Pharmacie, AP-HP, Hôpital Bichat-Claude-Bernard, F-75018 Paris, France 6 Service de Maladies Infectieuses, AP-HP, Hôpital Pitié-Salpêtrière, F-75013 Paris, France 7 INSERM U720, F-75013 Paris, France
Received 9 October 2008; returned 21 November 2008; revised 12 December 2008; accepted 8 January 2009
* Correspondence address. Laboratoire de Virologie, Hôpital Pitié-Salpêtrière, F-75013 Paris, France. Tel: +33-142177401; Fax: +33-142177411; E-mail: isabelle.malet{at}psl.aphp.fr
Objectives: Raltegravir is the first approved inhibitor of HIV-1 integrase (IN). In most patients, raltegravir failure is associated with mutations in the IN gene, through two different genetic pathways: 155 (N155H) or 148 (Q148K/R/H). The objective of this study was to characterize the dynamics of HIV-1 quasispecies variant populations in patients who failed to respond to raltegravir treatment.
Patients and methods: Bulk genotyping and clonal analysis were performed during the follow-up of 10 patients who failed to respond to raltegravir treatment.
Results: Treatment failed through the 155 pathway in six patients and through the 148 pathway in two patients; two further patients switched from the 155 to the 148 pathway. In the two patients switching from the 155 to the 148 pathway, clonal analysis showed that Q148R/H and N155H mutations were present on different strands, suggesting that these two pathways are independent. This was consistent with our finding that each genetic profile was associated with different secondary mutations. We observed a greater variability among quasispecies associated with the 155 pathway, and IC50 determinations showed that the fold resistance to raltegravir, relative to wild-type, was 10 for the N155H mutant and 50 for the G140S+Q148H mutant.
Conclusions: Clonal analysis strongly suggests that the two main genetic pathways, 155 and 148, involved in the development of resistance to raltegravir are independent and exclusive. Moreover, the switch of the resistance profile from 155 to 148 may be related to the higher level of resistance to raltegravir conferred by the 148 pathway and also to the higher instability of the 155 pathway.
Keywords: integrase , clonal analysis , drug resistance
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  M. Wirden, A. Simon, L. Schneider, R. Tubiana, I. Malet, H. Ait-Mohand, G. Peytavin, C. Katlama, V. Calvez, and A.-G. Marcelin Raltegravir has no residual antiviral activity in vivo against HIV-1 with resistance-associated mutations to this drug J. Antimicrob. Chemother., November 1, 2009; 64(5): 1087 - 1090. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Fransen, M. Karmochkine, W. Huang, L. Weiss, C. J. Petropoulos, and C. Charpentier Longitudinal Analysis of Raltegravir Susceptibility and Integrase Replication Capacity of Human Immunodeficiency Virus Type 1 during Virologic Failure Antimicrob. Agents Chemother., October 1, 2009; 53(10): 4522 - 4524. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. Quercia, E. Dam, D. Perez-Bercoff, and F. Clavel Selective-Advantage Profile of Human Immunodeficiency Virus Type 1 Integrase Mutants Explains In Vivo Evolution of Raltegravir Resistance Genotypes J. Virol., October 1, 2009; 83(19): 10245 - 10249. [Abstract] [Full Text] [PDF]
|
|