Inhibition of CCR5-dependent HIV-1 infection by hairpin ribozyme gene therapy against CC-chemokine receptor 5.
CCR-5 is a major cellular coreceptor for R5 strains of HIV-1. Individuals carrying a homozygous 32-base-pair deletion in this gene are apparently healthy and are relatively resistant to HIV-1 infection. Since CCR5 appears to be dispensable for the host, but important for initial HIV-1 infection, CCR5 mRNA is an excellent therapeutic target for inhibiting HIV-1 replication via ribozyme knockout. We report here that hairpin ribozymes are able to reduce cellular CCR5 mRNA and cell surface CCR5 when stably introduced into PM1 cells by transduction with recombinant adenoassociated viral vector. The ribozymes effectively protect the cells from infection by R5 HIV-1 strains or non-syncytium-inducing clinical isolates commensurate with a reduction in CCR5 mRNA. These results suggest a novel gene therapy approach to preventing or slowing the disease progression of HIV-1 infection.
Feng
Y
Y
Immusol Inc., 10790 Roselle Street, San Diego, California, 92121, USA.
Leavitt
M
M
Tritz
R
R
Duarte
E
E
Kang
D
D
Mamounas
M
M
Gilles
P
P
Wong-Staal
F
F
Kennedy
S
S
Merson
J
J
Yu
M
M
Barber
J R
JR
D065100:CCR5 Receptor Antagonists; D002460:Cell Line; D015316:Genetic Therapy; D015497:HIV-1 / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D007700:Kinetics; D008561:Membrane Fusion / Q000187:drug effects; D009690:Nucleic Acid Conformation; D016337:RNA, Catalytic / Q000737:chemistry / Q000235:genetics* / Q000494:pharmacology; D012333:RNA, Messenger / Q000037:antagonists & inhibitors / Q000378:metabolism; D019713:Receptors, CCR5 / Q000235:genetics / Q000378:metabolism
D065100:CCR5 Receptor Antagonists; D016337:RNA, Catalytic; D012333:RNA, Messenger; D019713:Receptors, CCR5