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.
The calculated genetic barrier for antiretroviral drug resistance substitutions is largely similar for different HIV-1 subtypes / D.A. van de Vijver, A.M. Wensing, G. Angarano, B. Asjö, C. Balotta, E. Boeri, R. Camacho, M.L. Chaix, D. Costagliola, A. De Luca, I. Derdelinckx, Z. Grossman, O. Hamouda, A. Hatzakis, R. Hemmer, A. Hoepelman, A. Horban, K. Korn, C. Kücherer, T. Leitner, C. Loveday, E. MacRae, I. Maljkovic, C. de Mendoza, L. Meyer, C. Nielsen, E.L. Op de Coul, V. Ormaasen, D. Paraskevis, L. Perrin, E. Puchhammer-Stöckl, L. Ruiz, M. Salminen, J.C. Schmit, F. Schneider, R. Schuurman, V. Soriano, G. Stanczak, M. Stanojevic, A.M. Vandamme, K. Van Laethem, M. Violin, K. Wilbe, S. Yerly, M. Zazzi, C.A. Boucher. - In: JOURNAL OF ACQUIRED IMMUNE DEFICIENCY SYNDROMES. - ISSN 1525-4135. - 41:3(2006 Mar), pp. 352-360.
The calculated genetic barrier for antiretroviral drug resistance substitutions is largely similar for different HIV-1 subtypes
C. Balotta;
2006
Abstract
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.
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