The Calculated Genetic Barrier for Antiretroviral Drug Resistance Substitutions Is Largely Similar for Different HIV-1 Subtypes

Background: The genetic barrier, defined as the number of mutations required to overcome drug-selective pressure, is an important factor for the development of HIV drug resistance. Because of high variability between subtypes, particular HIV-1 subtypes could have different genetic barriers for drug resistance substitutions. This study compared the genetic barrier between subtypes using some 2000 HIV-1 sequences (>600 of non-B subtype) isolated from anti-retroviral-naive patients in Europe. Methods: The genetic barrier was calculated as the sum of transitions (scored as 1) and/or transversions (2.5) required for evolution to any major drug resistance substitution. In addition, the number of minor protease substitutions was determined for every subtype. Results: Few dissimilarities were found. An increased genetic barrier was calculated for I82A (subtypes C and G), V108I (subtype G), V118I (subtype G), Q151M (subtypes D and F), L210W (subtypes C, F, G, and CRF02_AG), and P225H (subtype A) (P < 0.001 compared with subtype B). A decreased genetic barrier was found for I82T (subtypes C and G) and V106M (subtype C) (P < 0.001 vs subtype B). Conversely, minor protease substitutions differed extensively between subtypes. Conclusions: Based on the calculated genetic barrier, the rate of drug resistance development may be similar for different HIV-1 subtypes. Because of differences in minor protease substitutions, protease inhibitor resistance could be enhanced in particular subtypes once the relevant major substitutions are selected.

Klaus Korn | Anne-Mieke Vandamme | Sabine Yerly | Andy Hoepelman | Inge Derdelinckx | Lidia Ruiz | Luc Perrin | Maurizio Zazzi | Laurence Meyer | Elisabeth Puchhammer-Stöckl | Zehava Grossman | Mika Salminen | Dimitris Paraskevis | Francois Schneider | Angelos Hatzakis | Andrea De Luca | Kristel Van Laethem | Rob Schuurman | Jean-Claude Schmit | Clive Loveday | A. Wensing | K. Korn | L. Ruiz | S. Yerly | L. Perrin | V. Soriano | C. Loveday | A. Vandamme | G. Stańczak | T. Leitner | M. Salminen | C. Boucher | D. Paraskevis | A. Hatzakis | R. Camacho | Z. Grossman | K. Van Laethem | E. Puchhammer-Stöckl | M. Zazzi | D. Costagliola | A. De Luca | A. Horban | L. Meyer | E. O. D. Op de Coul | O. Hamouda | D. A. van de Vijver | J. Schmit | C. Balotta | C. Nielsen | R. Schuurman | M. Stanojevic | I. Derdelinckx | C. de Mendoza | Dominique Costagliola | Ricardo Camacho | M. Chaix | Thomas Leitner | Carmen de Mendoza | G. Angarano | Osamah Hamouda | Grzegorz Stanczak | E. Macrae | Vincent Soriano | A. Hoepelman | Marie-Laure Chaix | F. Schneider | E. Boeri | I. Maljkovic | Enzo Boeri | Gioacchino Angarano | Karin Wilbe | Birgitta Asjö | Robert Hemmer | Andrzej Horban | Claus Nielsen | Maja Stanojevic | Karin Wilbe | Claudia Balotta | Claudia Kücherer | Annemarie M J Wensing | Charles A B Boucher | David A van de Vijver | Eilidh MacRae | Irina Maljkovic | Eline L M Op de Coul | Vidar Ormaasen | Michela Violin | R. Hemmer | V. Ormaasen | M. Violin | B. Åsjö | C. Kücherer | L. Ruíz

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