Department of Experimental Medicine and Surgery, University of Rome Tor Vergata, Rome, Italy.
INMI 'L. Spallanzani', Rome, Italy.
J Antimicrob Chemother. 2014 Sep;69(9):2412-9. doi: 10.1093/jac/dku144. Epub 2014 May 23.
To evaluate the replication capacity and phenotypic susceptibility to dolutegravir and raltegravir of wild-type and raltegravir-resistant HIV-1 strains in several cellular systems.
The antiviral activities of dolutegravir and raltegravir were evaluated in human primary monocyte-derived macrophages (MDMs), peripheral blood mononuclear cells (PBMCs) and C8166 T lymphocytic cells. The following raltegravir resistance mutations were analysed: N155H, Y143C, N155H + Y143C and G140S+Q148H.
In the absence of drug, the replication capacity of raltegravir-resistant viruses was strongly reduced compared with wild-type in all cellular models analysed. In MDMs and PBMCs, a dramatic decrease in viral replication was observed for the double mutants N155H + Y143C and G140S + Q148H (ranging from 0.1% to 2.5% compared with wild-type). In MDMs, dolutegravir exhibited high potency, with EC50 and EC90 values of 1.1 ± 0.9 and 5.5 ± 3.4 nM, respectively (comparable to raltegravir). These values (particularly for EC90) were significantly lower than those observed in PBMCs (EC50: 2.7 ± 1.5 nM; EC90: 14.8 ± 0.9 nM) and C8166 cells (EC50: 5.5 ± 0.8 nM; EC90: 64.8 ± 5.8 nM). In all cellular models analysed, dolutegravir showed full efficacy against N155H and Y143C mutants (dolutegravir fold-change resistance ranging from 0.1 to 1.4; raltegravir fold-change resistance ranging from 0.1 to 10.3). In C8166 (the only cell model in which replication capacity was sufficient to perform the test) dolutegravir showed full efficacy against mutations N155H + Y143C (dolutegravir fold-change resistance: 0.6) and a slightly lower activity against G140S+Q148H (dolutegravir fold-change resistance: 2.1).
Dolutegravir is effective in different HIV cellular targets and against raltegravir-resistant mutants. The high efficacy of dolutegravir in MDMs (cells with limited metabolism) has relevant clinical implications in light of the role of MDMs in the transmission of HIV infection and dissemination in different body compartments.
评估几种细胞系统中野生型和拉替拉韦耐药 HIV-1 株对多替拉韦和拉替拉韦的复制能力和表型敏感性。
在人原代单核细胞衍生的巨噬细胞（MDMs）、外周血单核细胞（PBMCs）和 C8166 T 淋巴细胞中评估多替拉韦和拉替拉韦的抗病毒活性。分析了以下拉替拉韦耐药突变：N155H、Y143C、N155H+Y143C 和 G140S+Q148H。
在没有药物的情况下，与所有分析的细胞模型中的野生型相比，拉替拉韦耐药病毒的复制能力在所有细胞模型中均受到强烈抑制。在 MDMs 和 PBMCs 中，双突变体 N155H+Y143C 和 G140S+Q148H 的病毒复制显著下降（与野生型相比，分别为 0.1%至 2.5%）。在 MDMs 中，多替拉韦表现出高活性，EC50 和 EC90 值分别为 1.1±0.9 和 5.5±3.4 nM（与拉替拉韦相当）。这些值（特别是 EC90）明显低于在 PBMCs（EC50：2.7±1.5 nM；EC90：14.8±0.9 nM）和 C8166 细胞（EC50：5.5±0.8 nM；EC90：64.8±5.8 nM）中观察到的值。在所有分析的细胞模型中，多替拉韦对 N155H 和 Y143C 突变体均显示出完全疗效（多替拉韦耐药倍数变化范围为 0.1 至 1.4；拉替拉韦耐药倍数变化范围为 0.1 至 10.3）。在 C8166（唯一复制能力足以进行试验的细胞模型）中，多替拉韦对突变体 N155H+Y143C 显示出完全疗效（多替拉韦耐药倍数变化：0.6），对 G140S+Q148H 的活性略低（多替拉韦耐药倍数变化：2.1）。
多替拉韦在不同的 HIV 细胞靶标和拉替拉韦耐药突变体中均有效。多替拉韦在 MDMs（代谢有限的细胞）中的高疗效具有重要的临床意义，因为 MDMs 在 HIV 感染的传播和在不同身体部位的扩散中发挥作用。
