Cilliers Tonie, Moore Penny, Coetzer Mia, Morris Lynn
AIDS Virus Research Unit, National Institute for Communicable Diseases, Johannesburg, South Africa.
AIDS Res Hum Retroviruses. 2005 Sep;21(9):776-83. doi: 10.1089/aid.2005.21.776.
Enfuvirtide (ENF) is the first in a new class of antiretroviral agents targeting the fusion process of the viral life cycle. ENF is a synthetic 36-amino acid peptide that binds to the HR-1 region of gp41 preventing fusion of viral and cellular membranes. With the introduction of ENF there are now four classes of antiretrovirals each with distinct and different resistance pathways. Resistance to ENF among subtype B HIV-1 isolates is associated with amino acid changes mainly in the HR-1 region, although other regions of envelope have also been implicated. To determine whether subtype C viruses developed resistance mutations similar to subtype B viruses, 11 subtype C and 4 subtype B viruses were passaged in the presence of increasing concentrations of ENF. The subtype C isolates showed varying levels of replication at 1 microg/ml ENF by day 18, but by day 29 all replicated efficiently at 10 microg/ml ENF. All subtype C isolates showed evidence of genotypic changes in gp41 HR-1 following exposure to ENF that included G36S/E/D, I37T, V38M/A/L/E, N/S42D, N43K, L45R/M, and A50T/V. Three subtype C viruses had compensatory changes in the HR-2 region, which corresponds to the ENF sequence, and two isolates had changes in the V3 region. Mutational patterns among the four subtype B viruses were similar to those for subtype C and those previously published in the literature. These data indicate that in vitro resistance to ENF develops rapidly among HIV-1 subtype C isolates. In general, mutational patterns for subtype C were similar to those described for subtype B, suggesting that the mechanism of action for ENF is similar for HIV-1 subtype B and C isolates.
恩夫韦肽（ENF）是一类新型抗逆转录病毒药物中的首个药物，这类药物靶向病毒生命周期的融合过程。ENF是一种合成的36个氨基酸的肽，它与gp41的HR-1区域结合，阻止病毒膜与细胞膜的融合。随着ENF的引入，现在有四类抗逆转录病毒药物，每类都有独特且不同的耐药途径。B型HIV-1分离株对ENF的耐药性与主要在HR-1区域的氨基酸变化有关，尽管包膜的其他区域也有牵连。为了确定C型病毒是否会产生与B型病毒类似的耐药突变，将11株C型和4株B型病毒在浓度不断增加的ENF存在下传代。C型分离株在第18天时在1微克/毫升ENF浓度下显示出不同水平的复制，但到第29天时，所有分离株在10微克/毫升ENF浓度下都能高效复制。所有C型分离株在暴露于ENF后，gp41 HR-1区域都显示出基因型变化的证据，包括G36S/E/D、I37T、V38M/A/L/E、N/S42D、N43K、L45R/M和A50T/V。三株C型病毒在与ENF序列对应的HR-2区域有补偿性变化，两株分离株在V3区域有变化。四株B型病毒的突变模式与C型病毒以及先前文献中报道的相似。这些数据表明，HIV-1 C型分离株在体外对ENF的耐药性迅速产生。总体而言，C型的突变模式与B型描述的相似，表明ENF对HIV-1 B型和C型分离株的作用机制相似。
