Moore John P, Kuritzkes Daniel R
Weill Medical College of Cornell University, New York, NY 10065, USA.
Curr Opin HIV AIDS. 2009 Mar;4(2):118-24. doi: 10.1097/COH.0b013e3283223d46.
Small molecule inhibitors targeting the CCR5 coreceptor represent a new class of drugs for treating HIV-1 infection. Maraviroc has received regulatory approvals, and vicriviroc is in phase 3 trials. Understanding how resistance to these drugs develops and is diagnosed is essential to guide clinical practice. We review what has been learned from in-vitro resistance studies, and how this relates to what is being seen, or can be anticipated, in clinical studies.
The principal resistance pathway in vitro involves continued use of CCR5 in an inhibitor-insensitive manner; the resistant viruses recognize the inhibitor-CCR5 complex, as well as free CCR5. Switching to use the CXCR4 coreceptor is rare. The principal genetic pathway involves accumulating 2-4 sequence changes in the gp120 V3 region, but a non-V3 pathway is also known. The limited information available from clinical studies suggests that a similar escape process is followed in vivo. However, the most common change associated with virologic failure involves expansion of pre-existing, CXCR4-using viruses that are insensitive to CCR5 inhibitors.
HIV-1 escapes small molecule CCR5 inhibitors by continuing to use CCR5 in an inhibitor-insensitive manner, or evades them by expanding naturally insensitive, CXCR4-using variants.
靶向CCR5共受体的小分子抑制剂代表了一类用于治疗HIV-1感染的新型药物。马拉维若已获得监管部门批准，维克维若正处于3期试验阶段。了解这些药物的耐药性如何产生以及如何诊断对于指导临床实践至关重要。我们回顾了从体外耐药性研究中获得的知识，以及这与临床研究中所见或可预期的情况之间的关系。
体外主要的耐药途径是以抑制剂不敏感的方式持续使用CCR5；耐药病毒既能识别抑制剂-CCR5复合物，也能识别游离的CCR5。转而使用CXCR4共受体的情况很少见。主要的遗传途径是在gp120 V3区域累积2至4个序列变化，但也存在非V3途径。临床研究中有限的信息表明，体内也会发生类似的逃逸过程。然而，与病毒学失败相关的最常见变化是对CCR5抑制剂不敏感的、预先存在的利用CXCR4的病毒的扩增。
HIV-1通过以抑制剂不敏感的方式持续使用CCR5来逃避小分子CCR5抑制剂，或者通过扩增天然不敏感的利用CXCR4的变体来躲避它们。
