HIV-1 亚型 CRF01_AE 和 B 中对整合酶抑制剂耐药性发展的遗传屏障。

Genetic barrier to the development of resistance to integrase inhibitors in HIV-1 subtypes CRF01_AE and B.

机构信息

Virology Department, INSERM U941-Paris 7 Diderot University, Saint-Louis Hospital-APHP, Paris, France.

出版信息

Intervirology. 2012;55(4):287-95. doi: 10.1159/000336658. Epub 2012 Mar 23.

DOI:10.1159/000336658

PMID:22456540

Abstract

OBJECTIVE

The genetic barrier for the evolution of integrase inhibitors (INIs) including raltegravir (RAL), elvitegravir (EVG), and dolutegravir (DTG) resistance was compared between HIV-1 subtypes CRF01_AE and B.

METHODS

Analysis of 66 substitutions associated with INI resistance at 41 amino acid positions in 144 nucleotide sequences (109 HIV-1 subtype CRF01_AE and 35 HIV-1 subtype B) of integrase-coding region of polymerase gene derived from INI-naive patients.

RESULTS

28/41 studied amino acid positions were conserved, leading to a similar genetic barrier between the two subtypes. At six codon positions with different genetic barriers, six mutations (V72I, L101I, A124T, T125K, and G140C/S) displayed a higher genetic barrier and one mutation (V201I) showed a lower genetic barrier in subtype CRF01_AE than subtype B.

CONCLUSIONS

Most studied amino acid positions including all corresponding to RAL and EVG primary mutations show a high level of conservation, indicating the same genetic barrier between subtypes CRF01_AE and B. Nevertheless, different genetic barriers were observed in two mutations described to be associated with DTG resistance (L101I, A124T) and other five RAL and EVG secondary mutations (V72I, T125K, G140C/S, V201I), which could have an impact on the development of resistance to RAL, EVG, and DTG.

摘要

目的

比较 HIV-1 型 CRF01_AE 和 B 亚型中整合酶抑制剂（INIs）包括拉替拉韦（RAL）、艾维雷格（EVG）和多替拉韦（DTG）耐药相关的遗传屏障。

方法

分析了来自未接受 INI 治疗的患者的聚合酶基因整合酶编码区的 144 个核苷酸序列（109 个 HIV-1 型 CRF01_AE 和 35 个 HIV-1 型 B）中与 INI 耐药相关的 66 个取代的 41 个氨基酸位置。

结果

在 41 个研究的氨基酸位置中，有 28 个位置是保守的，这导致了这两种亚型之间存在相似的遗传屏障。在六个遗传屏障不同的密码子位置，六种突变（V72I、L101I、A124T、T125K 和 G140C/S）在 CRF01_AE 亚型中的遗传屏障比 B 亚型高，而一种突变（V201I）则较低。

结论

包括所有对应于 RAL 和 EVG 主要突变的大多数研究氨基酸位置均显示出高度的保守性，表明 CRF01_AE 和 B 亚型之间存在相同的遗传屏障。然而，在与 DTG 耐药相关的两种突变（L101I、A124T）和其他五种 RAL 和 EVG 次要突变（V72I、T125K、G140C/S、V201I）中观察到不同的遗传屏障，这可能会对 RAL、EVG 和 DTG 的耐药性产生影响。