Genetic co-inactivation of macrophage- and T-tropic HIV-1 chemokine coreceptors CCR-5 and CXCR-4 by intrakines.
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.
Bai
X
X
Department of Cancer Biology, Comprehensive Cancer Center, Wake Forest University School of Medicine, Winston-Salem, NC 27157, USA.
Chen
J D
JD
Yang
A G
AG
Torti
F
F
Chen
S Y
SY
D002460:Cell Line; D018925:Chemokines / Q000235:genetics*; D019742:Chemokines, CC / Q000235:genetics; D019743:Chemokines, CXC / Q000235:genetics; D018014:Gene Transfer Techniques; D005818:Genetic Engineering; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors; D015658:HIV Infections / Q000378:metabolism / Q000517:prevention & control*; D015497:HIV-1; D006801:Humans; D008214:Lymphocytes / Q000276:immunology* / Q000378:metabolism; D019713:Receptors, CCR5 / Q000378:metabolism; D019718:Receptors, CXCR4 / Q000378:metabolism; D019707:Receptors, Chemokine / Q000378:metabolism*
D018925:Chemokines; D019742:Chemokines, CC; D019743:Chemokines, CXC; D019713:Receptors, CCR5; D019718:Receptors, CXCR4; D019707:Receptors, Chemokine