IrsiCaixa-HIVACAT, Institut de Recerca en Ciències de la Salut Germans Trias i Pujol (IGTP), Hospital Germans Trias, Universitat Autònoma de Barcelona, Catalonia, Spain.
Retrovirology. 2012 Feb 14;9:15. doi: 10.1186/1742-4690-9-15.
Resistance to the fusion inhibitor enfuvirtide (ENF) is achieved by changes in the gp41 subunit of the HIV envelope glycoprotein (Env). Specific ENF-associated mutational pathways correlate with immunological recovery, even after virological failure, suggesting that the acquisition of ENF resistance alters gp41 pathogenicity. To test this hypothesis, we have characterized the expression, fusion capability, induction of CD4+ T cell loss and single CD4+ T cell death of 48 gp41 proteins derived from three patients displaying different amino acids (N, T or I) at position 140 that developed a V38A mutation after ENF-based treatment.
In all cases, intra-patient comparison of Env isolated pre- or post-treatment showed comparable values of expression and fusogenic capacity. Furthermore, Env with either N or T at position 140 induced comparable losses of CD4+ T-cells, irrespective of the residue present at position 38. Conversely, Env acquiring the V38A mutation in a 140I background induced a significantly reduced loss of CD4+ T cells and lower single-cell death than did their baseline controls. No altered ability to induce single-cell death was observed in the other clones.
Overall, primary gp41 proteins with both V38A and N140I changes showed a reduced ability to induce single cell death and deplete CD4+ T cells, despite maintaining fusion activity. The specificity of this phenotype highlights the relevance of the genetic context to the cytopathic capacity of Env and the role of ENF-resistance mutations in modulating viral pathogenicity in vivo, further supporting the hypothesis that gp41 is a critical mediator of HIV pathogenesis.
HIV 包膜糖蛋白（Env）的 gp41 亚单位的变化导致对融合抑制剂恩夫韦肽（ENF）的耐药。特定的与 ENF 相关的突变途径与免疫恢复相关，即使在病毒学失败后也是如此，这表明获得 ENF 耐药性会改变 gp41 的致病性。为了验证这一假说，我们对来自三位患者的 48 种 gp41 蛋白进行了特征描述，这三位患者在接受基于 ENF 的治疗后，位置 140 出现了 V38A 突变，而位置 140 处的氨基酸（N、T 或 I）分别不同。
在所有情况下，患者治疗前后分离的 Env 的个体内比较均显示出可比较的表达和融合能力值。此外，位置 140 处具有 N 或 T 的 Env 诱导 CD4+T 细胞丢失的能力相当，而与位置 38 处的残基无关。相反，在 140I 背景下获得 V38A 突变的 Env 诱导 CD4+T 细胞的丢失明显减少，且比其基线对照的细胞死亡更低。在其他克隆中未观察到改变诱导单细胞死亡的能力。
总体而言，具有 V38A 和 N140I 改变的主要 gp41 蛋白尽管保持融合活性，但显示出降低诱导单细胞死亡和耗尽 CD4+T 细胞的能力。该表型的特异性突显了遗传背景对 Env 细胞病变能力的相关性以及 ENF 耐药突变在体内调节病毒致病性的作用，进一步支持了 gp41 是 HIV 发病机制的关键介质的假说。
