Potent inhibition of human immunodeficiency virus type 1 replication by conditionally replicating human immunodeficiency virus-based lentiviral vectors expressing envelope antisense mRNA.
We describe an HIV-based lentiviral vector that expresses a 1-kb antisense mRNA directed against the HIV-1 mRNAs containing env sequences. The expression of antisense env mRNAs (envAS) does not inhibit the synthesis of p24 expressed from the HIV-1 helper plasmid used to package the vector, as this helper has a deletion in the env gene. This allows the production of high-titer VSV-G pseudotyped lentiviral particles. In challenge experiments using unselected populations of SupT1 cells transduced with this vector, a complete inhibition of HIV-1 replication was observed for long periods of in vitro culture, even at high HIV-1 infectious doses. The potent inhibition of HIV-1 replication by this vector correlated with a low occurrence of mobilization of the vector to previously untransduced cells. The infectivity of the wild-type HIV-1 that escapes inhibition was highly inhibited, suggesting that the vector is providing HIV-1 inhibition of replication not only due to its antisense effect but also by competing for encapsidation and mobilization to noninfected cells.
Mautino
M R
MR
Clinical Gene Therapy Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892-1851, USA.
Morgan
R A
RA
D015152:Blotting, Northern; D015139:Blotting, Southern; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004797:Enzyme-Linked Immunosorbent Assay; D005822:Genetic Vectors; D015497:HIV-1 / Q000235:genetics* / Q000378:metabolism*; D016086:Lentivirus / Q000235:genetics*; D008957:Models, Genetic; D016376:Oligonucleotides, Antisense / Q000378:metabolism*; D010957:Plasmids / Q000378:metabolism; D016133:Polymerase Chain Reaction; D012333:RNA, Messenger / Q000378:metabolism*; D013997:Time Factors; D014161:Transduction, Genetic; D014162:Transfection; D014759:Viral Envelope Proteins / Q000235:genetics*
D016376:Oligonucleotides, Antisense; D012333:RNA, Messenger; D014759:Viral Envelope Proteins