Coevolution of RANTES sensitivity and mode of CCR5 receptor use by human immunodeficiency virus type 1 of the R5 phenotype
Coevolution of RANTES sensitivity and mode of CCR5 receptor use by human immunodeficiency virus type 1 of the R5 phenotype
复制标题
DOI：
10.1128/jvi.78.21.11807-11815.2004
复制
发表时间：
2004-11-01
影响因子：
5.4
通讯作者：
Fenyö, EM
中科院分区：
文献类型：
--
作者：
Karlsson, I;Antonsson, L;Fenyö, EM
人类免疫缺陷病毒1型（HIV-1）辅助受体使用的演变被描述为获得CXCR 4使用与加速疾病进展相关。然而，使用CXCR 4的病毒只能从大约一半患有进行性HIV-1疾病的个体中分离出来。另一半在整个疾病过程中继续仅产生使用CCR 5的病毒（R5表型）。在目前的工作中，CCR 5和CXCR 4之间的受体嵌合体的使用使我们能够研究HIV-1与R5表型的进化，这是没有发现的野生型辅助受体的使用的研究。总共测试了来自31个个体的246个分离株（173个具有R5表型）通过受体嵌合体感染细胞的能力。R5（窄）病毒能够仅使用野生型CCR 5，而R5（宽（1））至R5（宽（3））病毒能够分别使用1至3种嵌合受体。嵌合受体的广泛使用被解释为受体使用模式的灵活性增加。R5宽分离株在表达野生型CCR 5的细胞中表现出比R5（窄）分离株更高的感染性。此外，R5（广泛）分离株的灵活性增加伴随着对CC趋化因子RANTES抑制的敏感性降低。我们的研究结果表明HIV-1表型变化和致病过程之间存在密切关系，因为CCR 5使用的模式和效率以及分离病毒的RANTES敏感性的降低与患者的CD 4（+）-T细胞下降显著相关。一种可能的解释是，配体在CCR 5受体上的竞争或CCR 5可用性的改变可能会影响HIV-1感染的结果。
The evolution of human immunodeficiency virus type 1 (HIV-1) coreceptor use has been described as the acquisition of CXCR4 use linked to accelerated disease progression. However, CXCR4-using virus can be isolated only from approximately one-half of individuals with progressive HIV-1 disease. The other half continue to yield only CCR5-using viruses (R5 phenotype) throughout the course of disease. In the present work, the use of receptor chimeras between CCR5 and CXCR4 allowed us to study the evolution of HIV-1 with the R5 phenotype, which was not revealed by studies of wild-type coreceptor use. All together, 246 isolates (173 with the R5 phenotype) from 31 individuals were tested for their ability to infect cells through receptor chimeras. R5(narrow) virus was able to use only wild-type CCR5, whereas R5(broad(1)) to R5(broad(3)) viruses were able to use one to three chimeric receptors, respectively. Broad use of chimeric receptors was interpreted as an increased flexibility in the mode of receptor use. R5 broad isolates showed higher infectivity in cells expressing wild-type CCR5 than R5(narrow) isolates. Also, the increased flexibility of R5(broad) isolates was concomitant with a lower sensitivity to inhibition by the CC chemokine RANTES. Our results indicate a close relationship between HIV-1 phenotypic changes and the pathogenic process, since the mode and efficiency of CCR5 use as well as the decrease in the RANTES sensitivities of isolated viruses are significantly correlated with CD4(+)-T-cell decline in a patient. One possible explanation is that ligand competition at the CCR5 receptor or changed CCR5 availability may shape the outcome of HIV-1 infection.