Oliveira A C A, Martins A N, Pires A F N P C, Arruda M B, Tanuri A, Pereira H S, Brindeiro R M
Laboratory of Molecular Virology, Department of Genetics, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil.
AIDS Res Hum Retroviruses. 2009 Feb;25(2):193-8. doi: 10.1089/aid.2008.0160.
The synthetic peptide T-20 (enfuvirtide, EFV) represents the first compound approved by the FDA known as entry inhibitors (EIs). The resistance mutations associated with this new class of antiretroviral drug are located in the first heptad repeat (HR1) region of gp41. Amino acid changes in codons G36D/S, I37V, V38A/M/E, Q39H/R, Q40H, N42T, and N43D can confer resistance to EFV. In this work we investigated the presence of resistance mutations that occur in patients never treated with EFV and failing HAART with protease inhibitors (PIs), nucleoside reverse transcriptase (RT) inhibitors (NRTIs), and nonnucleoside RT inhibitors (NNRTIs). This knowledge can reveal whether this salvage therapy can be effective in patients failing HAART. For this, we amplified 65 samples from plasma isolates and than sequenced a fragment of 416 nt encompassing the HR1 and HR2 regions (amino acids 33-170 of gp41). The subtype distribution among the 65 isolates was 45 (69.23%) subtype B, 9 (13.85%) subtype C, 7 (10.77%) subtype F1, and 4 (6.15%) mosaics B/F1, B/C, F1/C, and C/F1/B. We found a high prevalence (7.6%) of EFV-associated mutation G36D in this cohort of patients failing HAART therapy, five isolates from subtype B (11.11% within this group). In contrast, when 1079 sequences from drug-naive patients were analyzed, only one showed the G36D substitution. This finding indicates a strong association between the selected position G36D and HAART therapy (p < 0.0001). The isolates that possess these mutations can develop resistance to EFV more rapidly. Nevertheless, more information about the impact of these mutations in salvage therapy with EFV in patients failing HAART must still be obtained.
合成肽T-20（恩夫韦肽，EFV）是美国食品药品监督管理局（FDA）批准的首个被称为进入抑制剂（EI）的化合物。与这类新型抗逆转录病毒药物相关的耐药性突变位于gp41的第一个七肽重复序列（HR1）区域。密码子G36D/S、I37V、V38A/M/E、Q39H/R、Q40H、N42T和N43D中的氨基酸变化可导致对EFV产生耐药性。在本研究中，我们调查了从未接受过EFV治疗且接受蛋白酶抑制剂（PI）、核苷类逆转录酶（RT）抑制剂（NRTI）和非核苷类RT抑制剂（NNRTI）治疗后高效抗逆转录病毒治疗（HAART）失败的患者中出现的耐药性突变情况。这些信息可以揭示这种挽救治疗对HAART失败的患者是否有效。为此，我们从血浆分离物中扩增了65个样本，然后对包含HR1和HR2区域（gp41的氨基酸33 - 170）的416 nt片段进行测序。65个分离株中的亚型分布为45个（69.23%）B亚型、9个（13.85%）C亚型、7个（10.77%）F1亚型和4个（6.15%）B/F1、B/C、F1/C和C/F1/B嵌合亚型。我们发现，在这群HAART治疗失败的患者中，EFV相关突变G36D的发生率很高（7.6%），其中有5个来自B亚型的分离株（在该组中占11.11%）。相比之下，当分析1079例初治患者的序列时，只有1例出现G36D替代。这一发现表明所选位置G36D与HAART治疗之间存在密切关联（p < 0.0001）。具有这些突变的分离株可能会更快地对EFV产生耐药性。然而，关于这些突变对HAART失败患者使用EFV进行挽救治疗的影响，仍需获取更多信息。
