Maïga Almoustapha-Issiaka, Malet Isabelle, Soulie Cathia, Derache Anne, Koita Victoria, Amellal Bahia, Tchertanov Luba, Delelis Olivier, Morand-Joubert Laurence, Mouscadet Jean-François, Murphy Robert, Cissé Mamadou, Katlama Christine, Calvez Vincent, Marcelin Anne-Genevieve
Department of Virology, Pitié-Salpêtrière Hospital, AP-HP, EA 2387, Universite Pierre et Marie Curie, Paris, France.
Antivir Ther. 2009;14(1):123-9.
HIV type-1 (HIV-1) integrase (IN) inhibitor resistance is the consequence of mutations that are selected in the viral IN gene targeted by antiretroviral drugs, such as raltegravir (RAL) and elvitegravir (EVG). The genetic barrier, defined as the number of viral mutations required to overcome the drug-selective pressure, is one of the important factors in the development of drug resistance. The genetic barrier for IN inhibitor resistance was compared between HIV-1 subtype B and HIV-1 subtype CRF02_AG, which is highly prevalent in West Africa and becoming more frequent in developed countries.
IN nucleotide sequences from 73 HIV-1 subtype B and 77 HIV-1 subtype CRF02_AG antiretroviral-naive patients were examined at 19 IN amino acid positions implicated in RAL and EVG resistance.
The majority (14/19) of the studied positions showed a high degree of conservation of the predominant codon sequences leading to a similar genetic barrier between subtypes B and CRF02_AG. Nevertheless, at positions 140 and 151, the variability between subtypes affected the genetic barrier for the mutations G140C, G140S and V1511 with a higher genetic barrier being calculated for subtype CRF02_AG.
The major IN mutations E92Q, Q148K/R/H, N155H and E157Q (implicated in the resistance of IN inhibitors RAL and EVG) are highly conserved between subtypes B and CRF02_AG and display a similar genetic barrier. However, subtype CRFO2_AG showed a higher genetic barrier to acquire mutations 6140S, 6140C and V1511 as compared with subtype B, which could play a role in the resistance to RAL and/or EV6.
1型人类免疫缺陷病毒（HIV-1）整合酶（IN）抑制剂耐药性是由抗逆转录病毒药物（如拉替拉韦（RAL）和埃替拉韦（EVG））靶向的病毒IN基因中选择的突变导致的。遗传屏障定义为克服药物选择压力所需的病毒突变数量，是耐药性发展的重要因素之一。比较了HIV-1 B亚型和HIV-1 CRF02_AG亚型之间IN抑制剂耐药性的遗传屏障，CRF02_AG亚型在西非高度流行且在发达国家越来越常见。
对73例HIV-1 B亚型和77例未接受过抗逆转录病毒治疗的HIV-1 CRF02_AG亚型患者的IN核苷酸序列在与RAL和EVG耐药性相关的19个IN氨基酸位置进行检测。
所研究的大多数位置（14/19）显示主要密码子序列高度保守，导致B亚型和CRF02_AG亚型之间的遗传屏障相似。然而，在第140和151位，亚型之间的变异性影响了G140C、G140S和V151I突变的遗传屏障，计算得出CRF02_AG亚型的遗传屏障更高。
主要的IN突变E92Q、Q148K/R/H、N155H和E157Q（与IN抑制剂RAL和EVG的耐药性有关）在B亚型和CRF02_AG亚型之间高度保守且显示出相似的遗传屏障。然而，与B亚型相比，CRF02_AG亚型在获得6140S、6140C和V151I突变方面显示出更高的遗传屏障，这可能在对RAL和/或EVG的耐药性中起作用。
