McGill University AIDS Centre, Lady Davis for Medical Research, Jewish General Hospital, Montreal, Quebec, Canada.
Curr Infect Dis Rep. 2013 Feb;15(1):85-100. doi: 10.1007/s11908-012-0305-1.
This review focuses on the topic of HIV integrase inhibitors that are potent antiretroviral drugs that efficiently decrease viral load in patients. However, emergence of resistance mutations against this new class of drugs represents a threat to their long-term efficacy. Here, we provide new information about the most recent mutations identified and other mutations that confer resistance to several integrase inhibitors, such as new resistance mutations-for example, G118R, R263K, and S153Y-that have been identified through in vitro selection studies with second-generation integrase strand transfer inhibitors (INSTIs). These add to the three main resistance pathways involving mutations at positions Y143, N155, and Q148. Deep sequencing, structural modeling, and biochemical analyses are methods that currently help in the understanding of the mechanisms of resistance conferred by these mutations. Although the new resistance mutations appear to confer only low levels of cross-resistance to second-generation drugs, the Q148 pathway with numerous secondary mutations has the potential to significantly decrease susceptibility to all drugs of the INSTI family of compounds.
这篇综述的主题是 HIV 整合酶抑制剂，这些抑制剂是强效的抗逆转录病毒药物，能有效降低患者体内的病毒载量。然而，针对这一新类药物的耐药突变的出现，对其长期疗效构成了威胁。在这里，我们提供了有关最新鉴定的突变以及其他突变的新信息，这些突变对几种整合酶抑制剂具有耐药性，例如通过第二代整合酶链转移抑制剂（INSTIs）的体外选择研究中鉴定出的新耐药突变，例如 G118R、R263K 和 S153Y。这些突变增加了涉及位置 Y143、N155 和 Q148 的突变的三个主要耐药途径。深度测序、结构建模和生化分析是目前有助于理解这些突变赋予的耐药机制的方法。尽管新的耐药突变似乎仅对第二代药物表现出低水平的交叉耐药性，但具有许多次要突变的 Q148 途径有可能显著降低对所有 INSTI 类化合物药物的敏感性。
