UMR INSERM UPMC, Université Pierre et Marie Curie U 943, AP-HP, Hôpital Pitié Salpêtrière, Laboratoire de Virologie, Paris, France.
Curr Opin HIV AIDS. 2009 Nov;4(6):531-7. doi: 10.1097/COH.0b013e328331d4b1.
Understanding the mechanisms that underlie resistance development to novel drugs is essential to a better clinical management of resistant viruses and to prevent further resistance development and spread.
Integrase inhibitors and CCR5 antagonists are the more recent antiretroviral classes developed. The HIV-1 integrase, responsible for the chromosomal integration of the newly synthesized double-stranded viral DNA into the host genomic DNA, represents a new and important target; and two integrase inhibitors (INIs), raltegravir and elvitegravir, have been shown promising results in clinical trials. Viral entry is also an attractive step for the development of new drugs against HIV variants resistant to current antiretroviral drugs, and two CCR5 antagonists have been designed to inhibit HIV-1 binding to R5 co-receptor and are under clinical investigation.
Drug resistance to INIs occurs through the selection of mutations within HIV integrase. The kinetic of selection seems rapid and one mutation alone is able to confer resistance to integrase inhibitor, suggesting that this class of drug has a low genetic barrier. Two ways could explain the failure of the CCR5 antagonist class: a rapid outgrowth of pre-existing archived X4 virus or the selection of a resistance to CCR5 antagonists through amino acid changes in V3 loop.
了解新型药物耐药性产生的机制对于更好地临床管理耐药病毒以及防止进一步耐药性发展和传播至关重要。
整合酶抑制剂和 CCR5 拮抗剂是最近开发的抗逆转录病毒药物。HIV-1 整合酶负责将新合成的双链病毒 DNA 整合到宿主基因组 DNA 中，是一个新的重要靶点；两种整合酶抑制剂（INIs），raltegravir 和elvitegravir，在临床试验中显示出了有前途的结果。病毒进入也是开发针对对现有抗逆转录病毒药物耐药的 HIV 变异体的新药的一个有吸引力的步骤，两种 CCR5 拮抗剂已被设计用于抑制 HIV-1 与 R5 共受体的结合，并正在进行临床研究。
INIs 的耐药性是通过 HIV 整合酶内的突变选择产生的。选择的动力学似乎很快，单独一个突变就能使整合酶抑制剂产生耐药性，这表明这类药物的遗传屏障较低。CCR5 拮抗剂类药物失败的原因可能有两种：一是预先存在的 X4 病毒的大量生长；二是通过 V3 环的氨基酸变化选择对 CCR5 拮抗剂的耐药性。
