Defective lentiviral vectors are efficiently trafficked by HIV-1 and inhibit its replication.
Gene therapy against HIV infection should involve vector-mediated delivery of anti-HIV therapeutic genes into T-lymphocytes and macrophages or, alternatively, hematopoietic progenitors. Transduction of mature cells with defective vectors would have limited success because the vector would disappear with cell turnover. However, if a vector could be trafficked by wild-type HIV, initial transduction of a majority of the population would not be required, as the vector would be able to spread. We describe HIV-1-based lentiviral vectors that are efficiently packaged and trafficked by HIV-1, allowing a small number of cells initially transduced to spread the vector within a nontransduced cell population. We examined whether the presence or absence of the rev gene and the Rev-responsive element (RRE) would have a noticeable effect on the ability of lentiviral vectors to be trafficked and to inhibit HIV-1 replication. We found that replacement of rev/RRE with a constitutive transport element from Mason-Pfizer monkey virus had no apparent effect on trafficking and did not change the intrinsic inhibitory abilities of the vectors. We also constructed a rev/RRE-independent HIV-1-derived vector carrying a trans-dominant negative mutant of HIV-1 Rev, RevM10. This vector was less efficiently trafficked by HIV-1 and, despite the presence of an anti-HIV-1 gene, RevM10, was less efficient at inhibiting HIV-1 replication when introduced into a target T-cell population.
Klimatcheva
E
E
Department of Medicine, University of Rochester Cancer Center, 601 Elmwood Avenue, Rochester, New York 14642, USA.
Planelles
V
V
Day
S L
SL
Fulreader
F
F
Renda
M J
MJ
Rosenblatt
J
J
D002478:Cells, Cultured; D003673:Defective Viruses; D015694:Gene Products, rev / Q000037:antagonists & inhibitors / Q000378:metabolism*; D018014:Gene Transfer Techniques; D015752:Genes, env / Q000502:physiology; D015757:Genes, rev / Q000502:physiology; D015316:Genetic Therapy / Q000379:methods; D005822:Genetic Vectors; D015497:HIV-1 / Q000235:genetics / Q000254:growth & development / Q000502:physiology*; D006801:Humans; D016086:Lentivirus / Q000235:genetics*; D013601:T-Lymphocytes / Q000378:metabolism / Q000821:virology; D014161:Transduction, Genetic; D014407:Tumor Cells, Cultured; D019065:Virus Assembly; D014779:Virus Replication / Q000235:genetics*; D054321:rev Gene Products, Human Immunodeficiency Virus
D015694:Gene Products, rev; D054321:rev Gene Products, Human Immunodeficiency Virus