CD4-independent, CCR5-dependent infection of brain capillary endothelial cells by a neurovirulent simian immunodeficiency virus strain
CD4-independent, CCR5-dependent infection of brain capillary endothelial cells by a neurovirulent simian immunodeficiency virus strain
复制标题
DOI：
10.1073/pnas.94.26.14742
复制
发表时间：
1997-12-23
影响因子：
11.1
通讯作者：
Doms, RW
中科院分区：
文献类型：
--
作者：
Edinger, AL;Mankowski, JL;Doms, RW
脑毛细血管内皮细胞 (BCEC) 是 HIV-1 和猿猴免疫缺陷病毒 (SIV) 株在体外和体内的 CD4 独立感染的靶标。 BCEC 的感染可能为病毒进入中枢神经系统提供了一个入口，并可能破坏血脑屏障功能，导致艾滋病痴呆的发展。我们发现恒河猴BCEC表达参与HIV和SIV进入的趋化因子受体，包括CCR5、CCR3、CXCR4和STRL33，但不表达CCR2b、GPR1或GPR15。神经毒株 SIV/17E-Fr 对 BCEC 的感染在激活时被氨氧戊烷调节完全抑制，在配体存在或不存在的情况下正常 T 细胞表达和分泌，但不被嗜酸细胞趋化因子或 CD4 抗体抑制。我们发现 SIV/17E-Fr 和其他几种 SIV 毒株的包膜 (env) 蛋白介导 CD4 阴性、CCR5 阳性细胞的细胞间融合和病毒感染。相反，与表达辅助受体 STRL33、GPR1 和 GPR15 的细胞的融合是 CD4 依赖性的。这些结果表明，CCR5 可以作为 BCEC 中 SIV 的主要受体，并表明血脑屏障破坏和病毒进入中枢神经系统可能存在不依赖于 CD4 的机制。
Brain capillary endothelial cells (BCECs) are targets of CD4-independent infection by HIV-1 and simian immunodeficiency virus (SIV) strains in vitro and in vivo. Infection of BCECs may provide a portal of entry for the virus into the central nervous system and could disrupt blood-brain barrier function, contributing to the development of AIDS dementia. We found that rhesus macaque BCECs express chemokine receptors involved in HIV and SIV entry including CCR5, CCR3, CXCR4, and STRL33, but not CCR2b, GPR1, or GPR15. Infection of BCECs by the neurovirulent strain SIV/17E-Fr was completely inhibited by aminooxypentane regulation upon activation, normal T cell expression and secretion in the presence or absence of ligands, but not by eotaxin or antibodies to CD4. We found that the envelope (env) proteins from SIV/17E-Fr and several additional SIV strains mediated cell-cell fusion and virus infection with CD4-negative, CCR5-positive cells. In contrast, fusion with cells expressing the coreceptors STRL33, GPR1, and GPR15 was CD4-dependent. These results show that CCR5 can serve as a primary receptor for SIV in BCECs and suggest a possible CD4-independent mechanism for blood-brain barrier disruption and viral entry into the central nervous system.