In vitro phenotypes to elvitegravir and dolutegravir in primary macrophages and lymphocytes of clonal recombinant viral variants selected in patients failing raltegravir
In vitro phenotypes to elvitegravir and dolutegravir in primary macrophages and lymphocytes of clonal recombinant viral variants selected in patients failing raltegravir
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DOI：
10.1093/jac/dkt220
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发表时间：
2013-11-01
影响因子：
5.2
通讯作者：
Clementi, Massimo
中科院分区：
文献类型：
--
作者：
Canducci, Filippo;Ceresola, Elisa Rita;Clementi, Massimo
目的：埃替拉韦和度鲁特韦对雷特格韦耐药变异体的交叉耐药特征在巨噬细胞中仍然存在争议或不可用，并且缺乏对广泛的克隆变异体的广泛评价。因此，一个完整的评价平行与所有目前可用的整合酶抑制剂（INI）performed.Methods：整合酶编码区进行RT-PCR扩增从患者来源的血浆样品和克隆到HIV-1分子克隆缺乏整合酶区域。20个重组病毒携带突变的所有主要途径的耐雷特格韦进行了表型评价与每个整合酶抑制剂在新鲜纯化的CD 4 + T细胞或单核细胞来源的macrophage.Results：Y143 R单突变体赋予更高水平的雷特格韦耐药的巨噬细胞[倍数变化（FC）47.7-60.24]相比，CD 4 + T细胞（FC 9.55-11.56）。所有其他组合在两种细胞类型中对病毒对雷特格韦的敏感性具有相似的影响，Elvitegravir在淋巴细胞和巨噬细胞中显示出与所有测试模式相似的行为。与雷特格韦相比，Y143 R/C途径的耐药性未增加至中度增加。多鲁特韦在巨噬细胞中保持其活性和交叉耐药特征。仅Q148 H/R变异体的易感性水平降低（FC 5.48-18.64）。Y143 R/C（+/-T97 A）或N155 H variants.Conclusions：所有INI在两种细胞类型中显示出相当的抗逆转录病毒活性，即使单个突变与体外对雷特格韦和埃替格韦在巨噬细胞中的不同水平的敏感性相关。特别是，度鲁特韦能够以相似的效力抑制两种HIV-1主要细胞库中Y143或N155途径的雷特格韦耐药变异体的感染。
Objectives: The cross-resistance profiles of elvitegravir and dolutegravir on raltegravir-resistant variants is still controversial or not available in macrophages and lack extensive evaluations on wide panels of clonal variants. Thus, a complete evaluation in parallel with all currently available integrase inhibitors (INIs) was performed.Methods: The integrase coding region was RT-PCR-amplified from patient-derived plasma samples and cloned into an HIV-1 molecular clone lacking the integrase region. Twenty recombinant viruses bearing mutations to all primary pathways of resistance to raltegravir were phenotypically evaluated with each integrase inhibitor in freshly purified CD4+ T cells or monocyte-derived macrophages.Results: Y143R single mutants conferred a higher level of raltegravir resistance in macrophages [fold change (FC) 47.7-60.24] compared with CD4+ T cells (FC 9.55-11.56). All other combinations had similar effects on viral susceptibility to raltegravir in both cell types, Elvitegravir displayed a similar behaviour both in lymphocytes and macrophages with all the tested patterns. When compared with raltegravir, none to modest increases in resistance were observed for the Y143R/C pathways. Dolutegravir maintained its activity and cross-resistance profile in macrophages. Only Q148H/R variants had a reduced level of susceptibility (FC 5.48-18.64). No variations were observed for the Y143R/C (+/- T97A) or N155H variants.Conclusions: All INIs showed comparable antiretroviral activity in both cell types even if single mutations were associated with a different level of susceptibility in vitro to raltegravir and elvitegravir in macrophages. In particular, dolutegravir was capable of inhibiting with similar potency infection of raltegravir-resistant variants with Y143 or N155 pathways in both HIV-1 major cell reservoirs.