Bai X, Chen J D, Yang A G, Torti F, Chen S Y
Department of Cancer Biology, Comprehensive Cancer Center, Wake Forest University School of Medicine, Winston-Salem, NC 27157, USA.
Gene Ther. 1998 Jul;5(7):984-94. doi: 10.1038/sj.gt.3300667.
CC-chemokine receptor (CCR)-5 is the principal coreceptor for the entry of macrophage (M)-tropic HIV-1 viruses into a cell, while CXC-chemokine receptor (CXCR)-4 is the principal coreceptor for T cell line (T)-tropic HIV-1. In this study, we utilized a novel intracellular chemokine (intrakine) strategy to co-inactivate genetically both CCR-5 and CXCR-4 in human lymphocytes. The principle of co-inactivation of CCR-5 and CXCR-4 was illustrated by targeting the CC-intrakine and CXC-intrakine to the lumen of the endoplasmic reticulum (ER) for intracellular blockade of the transport of newly synthesized chemokine coreceptors to the cell surface. The lymphocytes with the phenotypic knock-out of CCR-5 and CXCR-4 were found broadly to resist the infection of M-tropic, T-tropic and dual-tropic HIV-1 viruses. Moreover, the transduced lymphocytes retained normal cell features, including the responsiveness to mitogen and recall antigen stimulation. Thus, this study to our knowledge, is the first to demonstrate that genetic co-inactivation of the M- and T-tropic HIV-1 principal coreceptors in lymphocytes or other cells could be a viable strategy for the long-term control of HIV-1 infection.
CC趋化因子受体（CCR）-5是嗜巨噬细胞型HIV-1病毒进入细胞的主要共受体，而CXC趋化因子受体（CXCR）-4是嗜T细胞系型HIV-1的主要共受体。在本研究中，我们采用了一种新型的细胞内趋化因子（intrakine）策略，在人淋巴细胞中对CCR-5和CXCR-4进行基因共失活。通过将CC-intrakine和CXC-intrakine靶向内质网（ER）腔，以细胞内阻断新合成的趋化因子共受体向细胞表面的转运，来说明CCR-5和CXCR-4共失活的原理。发现CCR-5和CXCR-4表型敲除的淋巴细胞广泛抵抗嗜巨噬细胞型、嗜T细胞系型和双嗜性HIV-1病毒的感染。此外，转导的淋巴细胞保留了正常的细胞特征，包括对有丝分裂原和回忆抗原刺激的反应性。因此，据我们所知，本研究首次证明在淋巴细胞或其他细胞中对嗜巨噬细胞型和嗜T细胞系型HIV-1主要共受体进行基因共失活可能是长期控制HIV-1感染的可行策略。
