Nora Tamara, Charpentier Charlotte, Tenaillon Olivier, Hoede Claire, Clavel François, Hance Allan J
INSERM U 552, Université Paris 7 - Denis Diderot, Faculté de Médecine Xavier Bichat, Paris, France.
J Virol. 2007 Jul;81(14):7620-8. doi: 10.1128/JVI.00083-07. Epub 2007 May 9.
Viral recombination has been postulated to play two roles in the development of human immunodeficiency virus (HIV) resistance to antiretroviral drugs. First, recombination has the capacity to associate resistance mutations expressed by distinct viruses, thereby contributing to the development of viruses with improved drug resistance. In addition, recombination could preserve diversity in regions outside those subject to strong selective pressure. In this study, we sought direct evidence for the occurrence of these processes in vivo by evaluating clonal virus populations obtained from the same patient before and after a treatment change that, while unsuccessful in controlling viral replication, led to the emergence of viruses expressing a different profile of resistance mutations. Phylogenetic studies supported the conclusion that the genotype arising after the treatment change resulted from the emergence of recombinant viruses carrying previously existing resistance mutations in novel combinations, whereas alternative explanations, including convergent evolution, were not consistent with observed genotypic changes. Despite evidence for a strong loss of genetic diversity in genomic regions coding for the protease and reverse transcriptase, diversity in regions coding for Gag and envelope was considerably higher, and recombination between the emerging viruses expressing the new pattern of resistance mutations and viral quasispecies in the previously dominant population contributed to this preservation of diversity in the envelope gene. These findings emphasize that recombination can participate in the adaptation of HIV to changing selective pressure, both by generating novel combinations of resistance mutations and by maintaining diversity in genomic regions outside those implicated in a selective sweep.
病毒重组被认为在人类免疫缺陷病毒（HIV）对抗逆转录病毒药物产生耐药性的过程中发挥着两种作用。首先，重组能够将不同病毒表达的耐药突变联系起来，从而促进具有更强耐药性的病毒的产生。此外，重组可以在那些受到强烈选择压力的区域之外保持多样性。在本研究中，我们通过评估在治疗改变前后从同一患者获得的克隆病毒群体，来寻找这些过程在体内发生的直接证据。此次治疗改变虽然未能成功控制病毒复制，但导致了表达不同耐药突变谱的病毒的出现。系统发育研究支持了这样的结论：治疗改变后出现的基因型是由携带先前存在的耐药突变的新型组合的重组病毒的出现所导致的，而包括趋同进化在内的其他解释与观察到的基因型变化并不一致。尽管有证据表明编码蛋白酶和逆转录酶的基因组区域的遗传多样性大幅丧失，但编码Gag和包膜蛋白的区域的多样性要高得多，并且表达新耐药突变模式的新兴病毒与先前占主导地位的群体中的病毒准种之间的重组促成了包膜基因中这种多样性的保留。这些发现强调，重组可以通过产生耐药突变的新型组合以及在与选择性清除无关的基因组区域维持多样性，参与HIV对不断变化的选择压力的适应。
