Carmona R, Pérez-Alvarez L, Muñoz M, Casado G, Delgado E, Sierra M, Thomson M, Vega Y, Vázquez de Parga E, Contreras G, Medrano L, Nájera R
Area de Patogenia Viral, Centro Nacional de Microbiología, Instituto de Salud Carlos III, Majadahonda, 28220 Madrid, Spain.
J Clin Virol. 2005 Mar;32(3):248-53. doi: 10.1016/j.jcv.2004.11.009.
The natural occurrence of primary resistance mutations in reverse transcriptase (RT) and protease (PR) genes of HIV-1 isolates from untreated patients has been reported and it may have important implications for the response to drug treatment. It is predictable that the same occurs in the HR1 region of gp41 sequence from patients who have never received T20 therapy, and in this regard it would be important to know not only the mutation frequencies at HR1 region but also the natural polymorphisms at resistance-associated positions present in the absence of this drug.
The objectives of this study are to investigate the existence of natural resistance-associated mutations to T20 in HR1 gp41 region corresponding to different HIV-1 genetic forms from T20 naive patients and to determine their prevalence.
Two hundred HIV-1 gp41 sequences were included: subtype B: 164 (81.3%); subtype A: 15 (8.2%); subtype G: 10 (4.6%); subtype F: 6 (3.5%); subtype C: 3 (1.8%); subtype K: 1 (0.6%); and subtype D: 1 (0.6%). We analyzed the resistance-associated mutations previously described: Q32H/R, G36D/S, I37V, V38A/M, Q39R/H, Q40H, N42T/D/Q/H, N43D/S/K/Q, L44M, L45M, R46M and V69I.
Natural resistance mutations to T20 were found at a high frequency: 10.5%, corresponding to 9.1% in subtype B and 16.7% in non-B subtype samples. Polymorphisms were more frequent in non-B and recombinant forms than in subtype B (p<0.001). Different substitutions were related to subtypes: N42S in subtypes A, B, G and C, but not in F, Q56R in subtype A from CRF02_AG, and L54M in subtype B from CRF14_BG.
To our knowledge this is the first study describing natural-resistance to T20 among different HIV-1 subtypes, warranting a study of the biological significance of this mutations and their clinical relevance. The detection of differences between subtypes may have an influence on the rate and patterns of resistance in patients undergoing T20 treatment.
有报道称，未经治疗患者的HIV-1分离株逆转录酶（RT）和蛋白酶（PR）基因中会自然出现原发性耐药突变，这可能对药物治疗反应具有重要影响。可以预测，从未接受过T20治疗的患者，其gp41序列的HR1区域也会出现同样的情况。在这方面，不仅了解HR1区域的突变频率，而且了解在未使用这种药物情况下耐药相关位点的自然多态性都很重要。
本研究的目的是调查初治T20患者中与不同HIV-1基因形式相对应的gp41 HR1区域中是否存在对T20的天然耐药相关突变，并确定其流行率。
纳入了200条HIV-1 gp41序列：B亚型：164条（81.3%）；A亚型：15条（8.2%）；G亚型：10条（4.6%）；F亚型：6条（3.5%）；C亚型：3条（1.8%）；K亚型：1条（0.6%）；D亚型：1条（0.6%）。我们分析了先前描述的耐药相关突变：Q32H/R、G36D/S、I37V、V38A/M、Q39R/H、Q40H、N42T/D/Q/H、N43D/S/K/Q、L44M、L45M、R46M和V69I。
发现对T20的天然耐药突变频率很高：为10.5%，其中B亚型为9.1%，非B亚型样本为16.7%。非B亚型和重组形式的多态性比B亚型更常见（p<0.001）。不同的替代与亚型有关：A、B、G和C亚型中有N42S，但F亚型中没有；CRF02_AG的A亚型中有Q56R；CRF14_BG的B亚型中有L54M。
据我们所知，这是第一项描述不同HIV-1亚型对T20天然耐药性的研究，有必要研究这种突变的生物学意义及其临床相关性。检测亚型之间的差异可能会影响接受T20治疗患者的耐药率和耐药模式。
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