Parikh Urvi M, Barnas Douglas C, Faruki Hawazin, Mellors John W
Department of Medicine, Division of Infectious Diseases, University of Pittsburgh School of Medicine, PA 15261, USA.
J Infect Dis. 2006 Sep 1;194(5):651-60. doi: 10.1086/505711. Epub 2006 Jul 24.
Prior virologic and biochemical studies have shown phenotypic antagonism between K65R and multiple thymidine-analogue mutations (TAMs) in site-directed mutants tested in vitro. We hypothesized, on the basis of this observed antagonism, that K65R and T215Y/F with multiple TAMs would not be selected on the same human immunodeficiency virus type 1 genome in vivo. We searched a large database of patient genotypes (n=59,262) for the frequency of K65R in combination with >or=3 TAMs as determined by standard population sequencing. K65R and multiple TAMs were rarely detected (<0.1%) in the same plasma sample. Samples with both K65R and >or=3 TAMs (n=21) were further analyzed by use of single-genome sequencing. K65R was never found on the same genome with T215F/Y and >or=2 other TAMs, except in the presence of the Q151M multiple nucleoside reverse-transcriptase inhibitor (NRTI)--resistance complex. These results indicate that antagonism between the K65R and T215Y/F pathways of NRTI resistance occurs at the genomic level. Therapy with NRTI combinations that select both pathways simultaneously may delay the emergence of NRTI resistance and prolong treatment response.
先前的病毒学和生物化学研究表明，在体外定点突变体中，K65R与多个胸苷类似物突变（TAMs）之间存在表型拮抗作用。基于观察到的这种拮抗作用，我们推测，在体内同一人类免疫缺陷病毒1型基因组上，K65R和带有多个TAMs的T215Y/F不会被同时选择。我们在一个大型患者基因型数据库（n = 59,262）中，通过标准群体测序来查找K65R与≥3个TAMs组合的频率。在同一血浆样本中很少检测到K65R和多个TAMs（<0.1%）。对同时具有K65R和≥3个TAMs的样本（n = 21）进一步采用单基因组测序进行分析。除了存在Q151M多个核苷类逆转录酶抑制剂（NRTI）耐药复合体的情况外，从未在同一基因组上发现K65R与T215F/Y以及≥2个其他TAMs同时存在。这些结果表明，NRTI耐药的K65R和T215Y/F途径之间的拮抗作用发生在基因组水平。同时选择这两种途径的NRTI联合治疗可能会延迟NRTI耐药的出现并延长治疗反应。
