van de Vijver David A, Wensing Annemarie M J, Angarano Gioacchino, Asjö Birgitta, Balotta Claudia, Boeri Enzo, Camacho Ricardo, Chaix Marie-Laure, Costagliola Dominique, De Luca Andrea, Derdelinckx Inge, Grossman Zehava, Hamouda Osamah, Hatzakis Angelos, Hemmer Robert, Hoepelman Andy, Horban Andrzej, Korn Klaus, Kücherer Claudia, Leitner Thomas, Loveday Clive, MacRae Eilidh, Maljkovic Irina, de Mendoza Carmen, Meyer Laurence, Nielsen Claus, Op de Coul Eline L M, Ormaasen Vidar, Paraskevis Dimitris, Perrin Luc, Puchhammer-Stöckl Elisabeth, Ruiz Lidia, Salminen Mika, Schmit Jean-Claude, Schneider Francois, Schuurman Rob, Soriano Vincent, Stanczak Grzegorz, Stanojevic Maja, Vandamme Anne-Mieke, Van Laethem Kristel, Violin Michela, Wilbe Karin, Yerly Sabine, Zazzi Maurizio, Boucher Charles A B
Eijkman Winkler Institute, Department of Virology, University Medical Center Utrecht, G04-614, 3584 CX Utrecht, the Netherlands.
J Acquir Immune Defic Syndr. 2006 Mar;41(3):352-60. doi: 10.1097/01.qai.0000209899.05126.e4.
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.
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.
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.
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.
遗传屏障定义为克服药物选择压力所需的突变数量，是HIV耐药性发展的一个重要因素。由于不同亚型之间的高度变异性，特定的HIV-1亚型可能对耐药性替代具有不同的遗传屏障。本研究使用从欧洲未接受过抗逆转录病毒治疗的患者中分离出的约2000个HIV-1序列（>600个非B亚型）比较了不同亚型之间的遗传屏障。
遗传屏障计算为进化到任何主要耐药性替代所需的转换（计为1分）和/或颠换（2.5分）的总和。此外，还确定了每个亚型的次要蛋白酶替代数量。
发现差异不大。计算得出I82A（C和G亚型）、V108I（G亚型）、V118I（G亚型）、Q151M（D和F亚型）、L210W（C、F、G和CRF02_AG亚型）和P225H（A亚型）的遗传屏障增加（与B亚型相比，P < 0.001）。发现I82T（C和G亚型）和V106M（C亚型）的遗传屏障降低（与B亚型相比，P < 0.001）。相反，不同亚型之间的次要蛋白酶替代差异很大。
根据计算出的遗传屏障，不同HIV-1亚型的耐药性发展速率可能相似。由于次要蛋白酶替代存在差异，一旦选择了相关的主要替代，特定亚型的蛋白酶抑制剂耐药性可能会增强。
