Cleland A, Watson H G, Robertson P, Ludlam C A, Brown A J
Centre for HIV Research, ICAPB, University of Edinburgh, Scotland.
J Acquir Immune Defic Syndr Hum Retrovirol. 1996 May 1;12(1):6-18. doi: 10.1097/00042560-199605010-00002.
Substantial differences have been described in the response of individual patients to zidovudine (ZDV) therapy, both in the clinical impact and in virus load. Genotypic changes associated with the appearance of drug resistance may also be different or occur at different rates. We have obtained the nucleotide sequence of the RT domain of individual HIV-1 genomes extracted from 10 plasma and peripheral blood mononuclear cell (PBMC) samples donated by two haemophiliac patients before, during, and after long-term ZDV therapy. Although the plasma virus load was similar throughout, the order and timing of appearance of resistance-associated substitutions differed in the two patients. In patient p74, K70R appeared after 4 months, T215Y at 5.5 months, and M41L at 13 months. In p87, K70R also appeared at 4 months, but T215Y and K219Q were not observed until 18 months and M41L not at all. Much greater sequence change overall occurred in p74. The evolution of the viral population in that patient was dominated by the unique appearance of T215Y and subsequently M41L, with all sequences from the last time point being descended by a single path from the pretreatment samples. However, in p87, several different lineages of RT sequences were found to persist throughout treatment. We propose that these differences in outcome may be determined by differences in genetic background at sites other than the five generally considered to be associated with ZDV sensitivity.
在接受齐多夫定（ZDV）治疗的个体患者中，无论是临床疗效还是病毒载量，都已发现存在显著差异。与耐药性出现相关的基因变化也可能不同或发生率各异。我们已获取了从两名血友病患者捐赠的10份血浆和外周血单核细胞（PBMC）样本中提取的个体HIV-1基因组RT结构域的核苷酸序列，这些样本分别来自长期ZDV治疗前、治疗期间及治疗后。尽管整个过程中血浆病毒载量相似，但两名患者中与耐药相关替代位点出现的顺序和时间有所不同。在患者p74中，K70R在4个月后出现，T215Y在5.5个月出现，M41L在13个月出现。在p87中，K70R同样在4个月出现，但T215Y和K219Q直到18个月才出现，而M41L根本未出现。总体而言，p74发生的序列变化要大得多。该患者病毒群体的进化以T215Y以及随后的M41L独特出现为主导，最后一个时间点的所有序列都通过单一途径从治疗前样本衍生而来。然而，在p87中，发现几种不同的RT序列谱系在整个治疗过程中持续存在。我们认为，这些结果差异可能由除通常认为与ZDV敏感性相关的五个位点之外的其他位点的遗传背景差异所决定。
