Lentiviral vector transduction of a dominant-negative Rev gene into human CD34+ hematopoietic progenitor cells potently inhibits human immunodeficiency virus-1 replication.
Gene therapy for human immunodeficiency virus (HIV)-1 may be performed by introducing into hematopoietic stem cells genes that inhibit replication of HIV-1 using lentiviral vectors. However, production of lentiviral vectors derived from HIV-1 may be inhibited by the gene being carried to inhibit HIV-1 and these vectors could be mobilized by wild-type HIV-1 infecting transduced cells. This study investigates these problems for the delivery of a dominant-negative rev gene humanized revM10 (huM10) by a lentiviral vector. Although most packaging plasmids suffered inhibition of expression of HIV-1 virion proteins by vectors expressing huM10, the packaging plasmids that expressed the highest levels of HIV-1 virion proteins produced vectors at titers that would be sufficient for clinical applications. The vectors carrying huM10 were used to transduce primary human CD34(+) hematopoietic progenitor cells and yielded high-level transduction without toxicity and conferred potent inhibition of HIV-1. The use of lentiviral vectors with deletion of the enhancers and promoter from the LTR (self-inactivating (SIN) vectors) decreased the frequency of vector mobilization by wild-type HIV-1; SIN vectors carrying huM10 were not mobilized detectably. These studies indicate that lentiviral vectors can be made effective for use in gene therapy for HIV-1.
Bahner
Ingrid
I
Division of Research Immunology/Bone Marrow Transplantation, The Saban Research Institute of Childrens Hospital Los angeles, Los Angeles, California, USA.
Sumiyoshi
Teiko
T
Kagoda
Mercy
M
Swartout
Robin
R
Peterson
Denise
D
Pepper
Karen
K
Dorey
Fred
F
Reiser
Jacob
J
Kohn
Donald B
DB
D018952:Antigens, CD34 / Q000378:metabolism*; D002460:Cell Line; D015694:Gene Products, rev / Q000235:genetics* / Q000378:metabolism*; D005822:Genetic Vectors / Q000235:genetics; D015497:HIV-1 / Q000502:physiology*; D006412:Hematopoietic Stem Cells / Q000378:metabolism*; D006801:Humans; D016086:Lentivirus / Q000235:genetics*; D010957:Plasmids / Q000235:genetics; D019076:Transgenes / Q000235:genetics; D014779:Virus Replication
D018952:Antigens, CD34; D015694:Gene Products, rev