Chong Huihui, Xu Sihong, Zhang Chuntao, Nie Jianhui, Wang Youchun
Institute of Pathogen Biology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
J Clin Virol. 2009 Jul;45(3):255-8. doi: 10.1016/j.jcv.2009.05.001. Epub 2009 May 31.
Although Enfuvirtide (T20) has not been used in China, investigating the natural occurrence of primary resistance mutations in the HR1 region of the gp41 sequence from T20 naïve patients would help in determining treatment strategies for AIDS patients.
To investigate natural mutations in the HR1 region of the gp41 sequence in China and evaluate their biological function.
The amino acid sequences in the HR1 region of 27 isolates including subtypes AE, BC and B' from Chinese T20 naïve patients were analyzed. All 27 isolates were constructed into pseudoviruses and their susceptibility to T20 was measured by using recombinant virus assays.
Mutations in a 10 amino acid motif, such as N42S and N42R, and those outside this motif, such as L33M, R46S, A50V, Q52H and L54M, were found in the 27 isolates. N in position 42 was mutated to S in all three AE subtype strains and 17 of 18 subtype BC strains, whilst it was mutated to R in all 6 subtypes B strains. Compared to the SF162 strain, the susceptibility of the mutants, except for L33M, to T20 was not significantly different. After L was mutated to M in position 33 of six strains by site directed mutagenesis, their IC50 values were increased by 3.7-7.9-fold.
Mutations outside a 10 amino acid motif in HR1, such as L33M, may cause T20 resistance.
尽管恩夫韦肽（T20）尚未在中国使用，但研究初治患者gp41序列HR1区原发性耐药突变的自然发生情况将有助于确定艾滋病患者的治疗策略。
研究中国患者gp41序列HR1区的自然突变并评估其生物学功能。
分析了来自中国初治患者的27株病毒株（包括AE、BC和B'亚型）gp41序列HR1区的氨基酸序列。将所有27株病毒株构建成假病毒，并通过重组病毒试验测定其对T20的敏感性。
在27株病毒株中发现了10个氨基酸基序内的突变，如N42S和N42R，以及该基序外的突变，如L33M、R46S、A50V、Q52H和L54M。在所有3株AE亚型毒株和18株BC亚型毒株中的17株中，42位的N突变为S，而在所有6株B亚型毒株中，42位的N突变为R。与SF162毒株相比，除L33M外，其他突变体对T20的敏感性无显著差异。通过定点诱变使6株毒株33位的L突变为M后，其半数抑制浓度（IC50）值增加了3.7至7.9倍。
HR1区10个氨基酸基序外的突变，如L33M，可能导致对T20耐药。
