Salgado María, Toro Carlos, Simón Ainhoa, Garrido Carolina, Blanco Francisco, Soriano Vincent, Rodés Berta
Service of Infectious Diseases, Hospital Carlos III, Madrid, Spain.
J Clin Virol. 2009 Oct;46(2):173-5. doi: 10.1016/j.jcv.2009.06.020. Epub 2009 Jul 22.
Raltegravir has been shown to be active against wildtype HIV-2 with a phenotypic susceptibility similar to HIV-1. Due to the recent introduction of these novel inhibitors, information on the selection of resistance mutations and its phenotypic effect in this population is scarce.
To explore in vitro the effect of raltegravir resistance in one individual with HIV-2 infection who failed raltegravir-HAART.
A 20-year-old man with HIV-2 infection received a raltegravir-based HAART regimen. Drug resistance mutations were examined in the integrase gene by sequence analysis. Phenotypic analyses were performed in two HIV-2 isolates from the patient (wildtype isolate: SP-2p2-175 and mutant isolate: SP-2p2-189) and a laboratory reference strain (HIV-2 ROD). Susceptibility to raltegravir was assessed in a PBMC culture assay. Furthermore, a replicative capacity assay was performed.
After introduction of raltegravir, patient's HIV-2 viremia dropped 1 log but did not reach undetectability. Genotypic analysis at month 8 with raltegravir, revealed the development of N155H resistant mutation along with other changes in the HIV-2 integrase: V72I, I84V, A153G, N160K and S163S/G. These changes resulted in a 37-fold increase in phenotypic resistance to raltegravir. Wildtype HIV-2 integrase (SP-2p2-175) had an IC(50) of 21.5nM and HIV-2 mutant virus (SP-2p2-189) showed an IC(50) of 789nM. SP-2p2-189 virus presented also lower replicative capacity in the absence of raltegravir than wildtype.
A continued low HIV-2 viral load seems to be enough to select the N155H mutation, which despite significantly impairing viral replication, shows a level of resistance sufficient to give a selective advantage to the virus that maintains this pathway of resistance to raltegravir overtime.
已证明雷特格韦对野生型HIV-2具有活性，其表型敏感性与HIV-1相似。由于最近引入了这些新型抑制剂，关于该人群中耐药突变的选择及其表型效应的信息很少。
在体外探讨雷特格韦耐药对一名接受雷特格韦-高效抗逆转录病毒治疗（HAART）失败的HIV-2感染者的影响。
一名20岁的HIV-2感染者接受了基于雷特格韦的HAART方案。通过序列分析检测整合酶基因中的耐药突变。对来自该患者的两种HIV-2分离株（野生型分离株：SP-2p2-175和突变型分离株：SP-2p2-189）以及一株实验室参考株（HIV-2 ROD）进行表型分析。在PBMC培养试验中评估对雷特格韦的敏感性。此外，进行了复制能力试验。
引入雷特格韦后，患者的HIV-2病毒血症下降了1个对数，但未降至检测不到的水平。在使用雷特格韦治疗8个月时进行的基因分析显示，出现了N155H耐药突变以及HIV-2整合酶的其他变化：V72I、I84V、A153G、N160K和S163S/G。这些变化导致对雷特格韦的表型耐药性增加了37倍。野生型HIV-2整合酶（SP-2p2-175）的IC50为21.5nM，HIV-2突变病毒（SP-2p2-189）的IC50为789nM。在没有雷特格韦的情况下，SP-2p2-189病毒的复制能力也低于野生型。
持续的低HIV-2病毒载量似乎足以选择N155H突变，该突变尽管显著损害病毒复制，但显示出足以使维持这种对雷特格韦耐药途径的病毒具有选择优势的耐药水平。
