Martínez-Cajas Jorge L, Pant-Pai Nitika, Klein Marina B, Wainberg Mark A
McGill University AIDS Centre, Lady Davis Institute for Medical Research, Jewish General Hospital, Montreal, Canada.
AIDS Rev. 2008 Oct-Dec;10(4):212-23.
The genetic diversity of HIV-1 has required its classification into types and subtypes. There is controversy as to how and to what extent genetic diversity may affect the emergence of antiretroviral drug resistance in HIV-1 subtypes other than B. To better understand the impact of genetic diversity (represented by different HIV-1 subtypes) on resistance to reverse transcriptase and protease inhibitor drugs, a systematic review was conducted on virologic and biochemical evidence obtained from work with non-B HIV-1 subtypes. We searched 11 databases and retrieved 3,486 citations on all aspects of non-B subtype-related resistance research. Twenty-seven studies with virologic and/or biochemical data met the eligibility criteria for our systematic review. Nineteen studies were found that reported phenotypes in non-B subtypes (304 from naive isolates and 242 from drug-exposed isolates) and 11 studies that used molecular biology techniques to study non-B resistance to antiretroviral drugs. Compared to the NL4-3 laboratory strain, lower baseline susceptibilities of recombinant A/G subtype virus to protease inhibitors were observed and a substantial proportion of subtype C isolates displayed higher IC50 at baseline for atazanavir. Some A/G isolates were found to have reduced susceptibility to abacavir. Mutations not typical of B subtypes include the reverse transcriptase mutation V106M and the protease mutations M89I/V and N83T. Virologic and biochemical data suggest that K65R is more likely to emerge in subtype C HIV-1. There is evidence to suggest differential effects of other mutations according to subtype, e.g. the protease inhibitor mutations I93L and M89I/V. Importantly, the most widely used commercial phenotyping systems do not take into account gag variations among natural isolates, which could limit the accuracy of measured susceptibility. Enzymatic and virologic data support the concept that naturally occurring polymorphisms in different non-B subtypes can affect the susceptibility of HIV-1 to different antiretroviral drugs, the magnitude of resistance conferred by major mutations, and the propensity to acquire some resistance mutations. Tools may need to be optimized to accurately measure drug susceptibility of non-B subtypes, especially for protease inhibitors.
HIV-1的基因多样性使其被分为不同类型和亚型。关于基因多样性如何以及在何种程度上影响除B型以外的HIV-1亚型中抗逆转录病毒药物耐药性的出现，存在争议。为了更好地理解基因多样性（以不同的HIV-1亚型表示）对逆转录酶和蛋白酶抑制剂药物耐药性的影响，我们对从非B型HIV-1亚型研究中获得的病毒学和生化证据进行了系统综述。我们检索了11个数据库，获取了3486篇关于非B亚型相关耐药性研究各方面的文献。27项具有病毒学和/或生化数据的研究符合我们系统综述的纳入标准。发现19项研究报告了非B亚型的表型（304份来自初治分离株，242份来自接受过药物治疗的分离株），11项研究使用分子生物学技术研究非B型对抗逆转录病毒药物的耐药性。与NL4-3实验室毒株相比，观察到重组A/G亚型病毒对蛋白酶抑制剂的基线敏感性较低，相当一部分C亚型分离株在基线时对阿扎那韦的IC50较高。发现一些A/G分离株对阿巴卡韦的敏感性降低。非B亚型特有的突变包括逆转录酶突变V106M和蛋白酶突变M89I/V和N83T。病毒学和生化数据表明，K65R更有可能出现在C型HIV-1中。有证据表明，其他突变根据亚型有不同的影响，例如蛋白酶抑制剂突变I93L和M89I/V。重要的是，最广泛使用的商业表型分析系统没有考虑天然分离株之间的gag变异，这可能会限制所测敏感性的准确性。酶学和病毒学数据支持这样的概念，即不同非B亚型中自然发生的多态性可以影响HIV-1对不同抗逆转录病毒药物的敏感性、主要突变赋予的耐药程度以及获得某些耐药突变的倾向。可能需要优化工具以准确测量非B亚型的药物敏感性，尤其是对于蛋白酶抑制剂。
