Specific mutations in HIV-1 gp41 are associated with immunological success in HIV-1-infected patients receiving enfuvirtide treatment
Specific mutations in HIV-1 gp41 are associated with immunological success in HIV-1-infected patients receiving enfuvirtide treatment
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DOI：
10.1093/jac/dkl306
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发表时间：
2006-10-01
影响因子：
5.2
通讯作者：
Perno, Carlo Federico
中科院分区：
文献类型：
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作者：
Aquaro, Stefano;D'Arrigo, Roberta;Perno, Carlo Federico
目的：研究54例HIV-1感染者在失败的治疗方案中加入单一活性药物恩富韦肽后gp41基因的变异性及其与病毒免疫学参数的相关性。方法：对54例接受恩富韦肽治疗的患者的102个HIV-1gp41基因序列和临床随访进行分析。结果：在第4周失败的方案中加入恩富韦肽后，病毒血症从5.1log(10)/m L下降到4.3log(10)/m L(P=0.0002)，CD_4从48个增加到106cell/m(3)(P=0.008)。病毒血症在第12周和第36周分别反弹到4.8和4.6log(10)/毫升，而CD4在第36周继续增加到136个细胞/毫米(3)。在接受恩夫韦德治疗的患者中，有45/54(83.3%)出现了在基线时很少发现的环境耐药突变。V38A/E是所有时间点最具代表性的突变。与V38A/E携带者相比，V38A/E携带者的CD_4细胞数在基线至24周时增加了4.5倍，在36周时增加了6倍(分别为P=0.004和0.02)，与病毒血症无明显相关性。相反，Q40H+L45M(在36周时存在于6名接受恩富韦肽治疗的患者中)与从基线到36周的CD4丢失相关(P=0.02)，与病毒血症无显著相关性。突变N126K(在6名接受恩福韦德治疗的患者中观察到，在基线时从未发现)取消了gp41糖基化第四位点，并与24周时CD4增加2.1倍相关。结论：特异性恩维菌素耐药突变(V38A/E)与CD4持续增加有关，对病毒血症无显著影响。由于病毒和免疫介导的机制很可能不适用于蛋白酶/逆转录酶抑制剂，这种CD4的恢复对于创新的治疗策略是重要的。
Objectives: To investigate gp41 variability and correlation with viro-immunological parameters in 54 HIV-1-infected patients receiving enfuvirtide added as single active drug to a failing regimen.Methods: One hundred and two HIV-1 gp41 sequences and clinical follow-up from 54 enfuvirtide-treated patients were analysed from baseline to week 36 of treatment. The association of mutations with viraemia/CD4 count was assessed by Mann-Whitney test.Results: The addition of enfuvirtide to the failing regimen induced at week 4 a viraemia decrease from 5.1 to 4.3 log(10)/mL (P = 0.0002) and a CD4 increase from 48 to 106 cells/mm(3) (P = 0.008). While viraemia rebounded to 4.8 and 4.6 log(10)/mL at week 12 and 36, respectively, CD4 continued to increase to 136 cells/mm(3) at week 36. Enfuvirtide resistance mutations, rarely found at baseline, occurred in 45/54 (83.3%) enfuvirtide-treated patients. V38A/E were the most represented mutations at all time-points. The presence of V38A/E was significantly associated with a 4.5-fold CD4 increase from baseline to week 24 and with a 6-fold increase at week 36 (P = 0.004 and 0.02 compared without V38A/E, respectively), without significant correlation with viraemia. In contrast, Q40H + L45M (present in six enfuvirtide-treated patients at week 36) correlated with CD4 loss from baseline to week 36 (P = 0.02), without significant correlation with viraemia. Mutation N126K (observed in six enfuvirtide-treated patients, never found at baseline) abrogates the fourth gp41 glycosylation site and correlates with a 2.1-fold CD4 increase at week 24.Conclusions: Specific enfuvirtide resistance mutations (V38A/E) are associated with a sustained CD4 increase, without remarkable effects upon viraemia. This CD4 recovery, due to virus- and immune-mediated mechanisms most probably not applicable to protease/reverse transcriptase inhibitors, is important for innovative therapeutic strategies.