Pacheco-Martínez Elena, Figueroa-Medina Evangelina, Villarreal Carlos, Cocho Germinal, Medina-Franco José L, Méndez-Lucio Oscar, Huerta Leonor
Programa de Maestría y Doctorado en Ciencias Bioquímicas, Universidad Nacional Autónoma de México, Ciudad Universitaria, Distrito Federal, 04510, México.
Unidad de Radio Oncología, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Secretaría de Salud, Avenida Vasco de Quiroga No.15, ᅟDistrito Federal, 14080, México.
Virol J. 2016 Feb 16;13:28. doi: 10.1186/s12985-016-0486-6.
The interaction of the envelope glycoprotein of HIV-1 (gp120/gp41) with coreceptor molecules has important implications for specific cellular targeting and pathogenesis. Experimental and theoretical evidences have shown a role for gp41 in coreceptor tropism, although there is no consensus about the positions involved. Here we analyze the association of physicochemical properties of gp41 amino acid residues with viral tropism (X4, R5, and R5X4) using a large set of HIV-1 sequences. Under the assumption that conserved regions define the complex structural features essential for protein function, we focused our search only on amino acids in the gp41 variable regions.
Gp41 amino acid sequences of 2823 HIV-1 strains from all clades with known coreceptor tropism were retrieved from Los Alamos HIV Database. Consensus sequences were constructed for homologous sequences (those obtained from the same patient and having the same tropism) in order to avoid bias due to sequence overrepresentation, and the variability (entropy) per site was determined. Comparisons of hydropathy index (HI) and charge (Q) of amino acid residues at highly variable positions between coreceptor groups were performed using two non-parametrical tests and Benjamini-Hochberg correction. Pearson's correlation analysis was performed to determine covariance of HI and Q values.
Calculation of variability per site rendered 58 highly variable amino acid positions. Of these, statistical analysis rendered significantly different HI or Q only for the R5 vs. R5X4 comparison at twelve positions: 535, 602, 619, 636, 640, 641, 658, 662, 667, 723, 756 and 841. The largest differences in particular amino acid frequencies between coreceptor groups were found at 619, 636, 640, 641, 662, 723 and 756. A hydrophobic tendency of residues 619, 640, 641, 723 and 756, along with a hydrophilic/charged tendency at residues 636 and 662 was observed in R5X4 with respect to R5 sequences. HI of position 640 covariated with that of 602, 619, 636, 662, and 756.
Variability and significant correlations of physicochemical properties with viral phenotype suggest that substitutions at residues in the loop (602 and 619), the HR2 (636, 640, 641, 662), and the C-terminal tail (723, 756) of gp41 may contribute to phenotype of R5X4 strains.
人类免疫缺陷病毒1型（HIV-1）包膜糖蛋白（gp120/gp41）与共受体分子的相互作用对于特定细胞靶向和发病机制具有重要意义。实验和理论证据表明gp41在共受体嗜性中发挥作用，尽管对于所涉及的位置尚无共识。在此，我们使用大量HIV-1序列分析gp41氨基酸残基的物理化学性质与病毒嗜性（X4、R5和R5X4）之间的关联。假设保守区域定义了蛋白质功能所必需的复杂结构特征，我们仅将搜索集中在gp41可变区域中的氨基酸上。
从洛斯阿拉莫斯HIV数据库中检索了来自所有分支且已知共受体嗜性的2823株HIV-1毒株的gp41氨基酸序列。为同源序列（那些来自同一患者且具有相同嗜性的序列）构建了共有序列，以避免由于序列过度代表而产生的偏差，并确定每个位点的变异性（熵）。使用两种非参数检验和Benjamini-Hochberg校正对共受体组之间高度可变位置的氨基酸残基的亲水性指数（HI）和电荷（Q）进行比较。进行Pearson相关分析以确定HI和Q值的协方差。
每个位点变异性的计算得出58个高度可变的氨基酸位置。其中，统计分析仅在12个位置（535、602、619、636、640、641、658、662、667、723、756和841）的R5与R5X4比较中得出了显著不同的HI或Q。共受体组之间特定氨基酸频率的最大差异出现在619、636、640、641、662、723和756。相对于R5序列，在R5X4中观察到619、640、641、723和756位残基的疏水倾向，以及636和662位残基的亲水/带电荷倾向。640位的HI与602、619、636、662和756位的HI协变。
变异性以及物理化学性质与病毒表型的显著相关性表明，gp41环（602和619）、HR2（636、640、641、662）和C末端尾巴（723、756）中残基的取代可能有助于R5X4毒株的表型。
