Adaptation to promiscuous usage of CC and CXC‐chemokine coreceptors in vivo correlates with HIV‐1 disease progression
Adaptation to promiscuous usage of CC and CXC‐chemokine coreceptors in vivo correlates with HIV‐1 disease progression
复制标题
体内对 CC 和 CXC 趋化因子辅助受体混用的适应与 HIV-1 疾病进展相关
DOI：
10.1097/00002030-199813000-00001
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发表时间：
1998
期刊：
影响因子：
3.8
通讯作者：
R. Lal
中科院分区：
文献类型：
--
作者：
L. Xiao;D. Rudolph;S. Owen;T. Spira;R. Lal
目的：通过对HIV-1感染者进行纵向随访，研究HIV-1原代分离株的辅助受体使用情况，以了解其在HIV疾病发病机制中的作用。设计：在不同的时间点检测HIV-1感染个体的连续原代分离株的病毒辅助受体使用情况，并将数据与CD 4细胞计数、疾病进展率和β-趋化因子产生进行比较。方法：从4个快速进展者、6个晚期进展者和3个长期非进展者（LTNP）中获得58个连续的原代分离株，并通过用野生型或无功能CC-趋化因子受体（CCR）-5感染来自供体的外周血单核细胞（PBMC）以及通过感染表达CD 4和各种趋化因子受体[CCR-1-CCR-5，CXC-趋化因子受体（CXCR）-4，BOB/GPR 15，BONZO/STRL 33]的GHOST 4细胞来检查其辅助受体使用。在感染期间的多个时间点，使用从这些个体分离的未经刺激或植物血凝素（PHA）刺激的PBMC检查RANTES和巨噬细胞炎性蛋白（MIP）-1β的产生。结果：从单一CCR-5辅助受体使用到多个辅助受体使用的转换发生在所有四个快速进展者和六个晚期进展者中的三个中。除了常用的辅助受体CXCR-4、CCR-5和CCR-3外，从感染终末期患者中分离的一些病毒也使用CCR-1、CCR-2b、CCR-4和BOB作为辅助受体。能够利用多种辅助受体的病毒变异体的出现通常先于CD 4细胞下降至< 200 × 106/l，并与AIDS的发病相关。相比之下，三个LTNP在感染后7-12年的时间内保持了CCR-5的独家使用。LTNP患者PBMC内源性产生RANTES和MIP-1β与快速和晚期进展者无显著差异。然而，PHA驱动的两种趋化因子的产生在LTNP中显著更高，这表明体内激活刺激可能通过诱导这些趋化因子来减少HIV复制。结论：能够利用广泛的辅助受体的病毒变体与HIV-1疾病进展相关。相比之下，LTNP维持CCR-5的排他性使用并产生更高水平的β-趋化因子。因此，病毒和宿主决定因素导致能够使用扩大范围的辅助受体的病毒变体的出现可能是疾病进展的决定因素。
Objective:To study coreceptor usage of sequential primary HIV-1 isolates in a longitudinal follow-up cohort of HIV-1-infected men to understand its contribution to pathogenesis of HIV disease. Design:Viral coreceptor usage of sequential primary isolates from HIV-1-infected individuals was examined at various timepoints and data was compared with CD4 cell counts, rates of disease progression and β-chemokine production. Methods:Fifty-eight sequential primary isolates were obtained from four rapid progressors, six late progressors, and three long-term nonprogressors (LTNP) and their coreceptor usage was examined by infection of peripheral blood mononuclear cells (PBMC) from donors with wild-type or non-functional CC-chemokine receptor (CCR)-5, and by infection of GHOST4 cells expressing CD4 and various chemokine receptors [CCR-1–CCR-5, CXC-chemokine receptor (CXCR)-4, BOB/GPR15, BONZO/STRL33]. Production of RANTES and macrophage inflammatory protein (MIP)-1β was examined using unstimulated or phytohemagglutinin (PHA)-stimulated PBMC isolated from these individuals at multiple timepoints during infection. Results:A switch from single CCR-5 coreceptor usage to multiple coreceptor usage occurred in all four rapid progressors and three out of six late progressors. In addition to the commonly used coreceptors CXCR-4, CCR-5, and CCR-3, some of the viruses isolated from patients in the terminal stage of infection also used CCR-1, CCR-2b, CCR-4, and BOB as coreceptors. The emergence of viral variants capable of utilizing multiple coreceptors generally preceded CD4 cell decline to < 200 × 106/l and correlated with the onset of AIDS. In contrast, three LTNP maintained exclusive usage of CCR-5 over a period of 7–12 years post-infection. Endogenous production of RANTES and MIP-1β by PBMC from LTNP was not significantly different from rapid and late progressors. However, PHA-driven production of both chemokines was significantly higher in LTNP, suggesting that in vivo activating stimuli might curtail HIV replication by inducing these chemokines. Conclusions:Viral variants capable of utilizing a broad range of coreceptors correlated with HIV-1 disease progression. In contrast, LTNP maintain exclusive usage of CCR-5 and produce higher levels of β-chemokines. Thus, both viral and host determinants leading to the emergence of viral variants capable of using an expanded range of coreceptors may be likely determinants of disease progression.
影响因子：
3.8
作者：
E. Berger
通讯作者：
E. Berger