Improved coreceptor usage prediction and genotypic monitoring of R5-to-X4 transition by motif analysis of human immunodeficiency virus type 1 env V3 loop sequences
Improved coreceptor usage prediction and genotypic monitoring of R5-to-X4 transition by motif analysis of human immunodeficiency virus type 1 env V3 loop sequences
复制标题
DOI：
10.1128/jvi.77.24.13376-13388.2003
复制
发表时间：
2003-12-01
影响因子：
5.4
通讯作者：
Mullins, JI
中科院分区：
文献类型：
--
作者：
Jensen, MA;Li, FS;Mullins, JI
在感染早期，人类免疫缺陷病毒1型（HIV-1）通常使用CCR5趋化因子受体（以及CD4）进入细胞。在许多hiv -1感染的个体中，病毒基因型发生变化，允许病毒使用CXCR4（除了CCR5外或单独使用）作为进入辅受体。这种转换与CD3(+) t细胞衰退和艾滋病进展的加速有关。众所周知，gp120的V3环在很大程度上决定了辅助受体的使用，V3中带正电的残基也起着重要作用，但V3基因改变导致辅助受体使用改变的过程尚不清楚。此外，用于研究或临床目的的病毒生物表型方法费力，依赖于样品的可用性，并且存在生物安全问题，因此需要可靠的基于序列的“虚拟表型”方法。我们介绍了一种简单的生物信息学方法，对V3氨基酸序列进行评分，可靠地预测CXCR4的使用（灵敏度为84%，特异性为96%）。该分数（根据位置特异性评分矩阵[PSSM]确定）可以解释为显示使用CXCR4的倾向如下：已知R5病毒得分低，R5X4病毒得分中等，X4病毒得分高。利用PSSM评分法重建11个纵向采样个体的病毒系统发育，发现X4病毒的发育总体上是渐进的，涉及V3中多个氨基酸变化的积累。我们发现X4病毒以两种方式消失：通过已建立的X4谱系的死亡或通过突变回到低得分的V3环。
Early in infection, human immunodeficiency virus type 1 (HIV-1) generally uses the CCR5 chemokine receptor (along with CD4) for cellular entry. In many HIV-1-infected individuals, viral genotypic changes arise that allow the virus to use CXCR4 (either in addition to CCR5 or alone) as an entry coreceptor. This switch has been associated with an acceleration of both CD3(+) T-cell decline and progression to AIDS. While it is well known that the V3 loop of gp120 largely determines coreceptor usage and that positively charged residues in V3 play an important role, the process of genetic change in V3 leading to altered coreceptor usage is not well understood. Further, the methods for biological phenotyping of virus for research or clinical purposes are laborious, depend on sample availability, and present biosafety concerns, so reliable methods for sequence-based "virtual phenotyping" are desirable. We introduce a simple bioinformatic method of scoring V3 amino acid sequences that reliably predicts CXCR4 usage (sensitivity, 84%; specificity, 96%). This score (as determined on the basis of position-specific scoring matrices [PSSM]) can be interpreted as revealing a propensity to use CXCR4 as follows: known R5 viruses had low scores, R5X4 viruses had intermediate scores, and X4 viruses had high scores. Application of the PSSM scoring method to reconstructed virus phylogenies of 11 longitudinally sampled individuals revealed that the development of X4 viruses was generally gradual and involved the accumulation of multiple amino acid changes in V3. We found that X4 viruses were lost in two ways: by the dying off of an established X4 lineage or by mutation back to low-scoring V3 loops.