Gasser Romain, Hamoudi Meriem, Pellicciotta Martina, Zhou Zhicheng, Visdeloup Clara, Colin Philippe, Braibant Martine, Lagane Bernard, Negroni Matteo
Architecture et Réactivité de l'ARN, Université de Strasbourg, CNRS, IBMC, 15 rue René Descartes, 67084, Strasbourg, France.
U1016, UMR 8104, INSERM-CNRS, Institut Cochin, Université Paris Descartes, Paris, France.
Retrovirology. 2016 Jul 30;13(1):50. doi: 10.1186/s12977-016-0285-6.
Covariation is an essential process that leads to coevolution of parts of proteins and genomes. In organisms subject to strong selective pressure, coevolution is central to keep the balance between the opposite requirements of antigenic variation and retention of functionality. Being the viral component most exposed to the external environment, the HIV-1 glycoprotein gp120 constitutes the main target of the immune response. Accordingly its more external portions are characterised by extensive sequence heterogeneity fostering constant antigenic variation.
We report that a single polymorphism, present at the level of the viral population in the conserved internal region C2, was sufficient to totally abolish Env functionality when introduced in an exogenous genetic context. The prominent defect of the non-functional protein is a block occurring after recognition of the co-receptor CCR5, likely due to an interference with the subsequent conformational changes that lead to membrane fusion. We also report that the presence of compensatory polymorphisms at the level of the external and hypervariable region V3 fully restored the functionality of the protein. The functional revertant presents different antigenic profiles and sensitivity to the entry inhibitor TAK 779.
Our data suggest that variable regions, besides harbouring intrinsic extensive antigenic diversity, can also contribute to sequence diversification in more structurally constrained parts of the gp120 by buffering the deleterious effect of polymorphisms, further increasing the genetic flexibility of the protein and the antigenic repertoire of the viral population.
共变是导致蛋白质和基因组部分共同进化的重要过程。在受到强烈选择压力的生物体中，共同进化对于在抗原变异和功能保留这两种相反需求之间保持平衡至关重要。作为最暴露于外部环境的病毒成分，HIV-1糖蛋白gp120构成免疫反应的主要靶标。因此，其更靠外的部分具有广泛的序列异质性，促进了持续的抗原变异。
我们报告，在保守的内部区域C2的病毒群体水平上存在的单个多态性，当引入外源基因背景时足以完全消除Env的功能。无功能蛋白的突出缺陷是在识别共受体CCR5后出现阻断，这可能是由于干扰了随后导致膜融合的构象变化。我们还报告，在外部高变区V3水平上存在的补偿性多态性完全恢复了该蛋白的功能。功能回复体呈现出不同的抗原谱和对进入抑制剂TAK 779的敏感性。
我们的数据表明，可变区除了具有内在的广泛抗原多样性外，还可以通过缓冲多态性的有害影响，在gp120结构上更受限制的部分促进序列多样化，进一步增加该蛋白的遗传灵活性和病毒群体的抗原库。
