A conditionally replicating HIV-based vector that stably expresses an antiviral shRNA against HIV-1 replication.
Human pathogenic viruses can be targeted by therapeutic strategies based on RNA interference. Whereas the administration of synthetic short interfering RNAs (siRNAs) may transiently inhibit viral replication, long-term inhibition may be achieved through stable intracellular expression of siRNAs or short hairpin RNAs (shRNAs). Both approaches face serious problems with delivery to the right cells in an infected individual. We explored the potential of a replicating HIV-based vector to deliver an antiviral shRNA cassette into HIV-1-susceptible target cells to block chronic HIV-1 infection. The vector is based on a doxycycline (dox)-dependent HIV-1 variant that we previously proposed as a conditional-live HIV-1 vaccine. With dox, this virus spreads efficiently to all HIV-susceptible cells. Subsequent dox withdrawal generates cells with a transcriptionally silent integrated provirus, but with an active shRNA expression cassette. Because the shRNA targets viral sequences that are removed from the vector construct, there is no self-targeting, yet there is specific shutdown of HIV-1 replication.
Westerhout
Ellen M
EM
Department of Human Retrovirology, Academic Medical Center, University of Amsterdam, Meibergdreef 15, 1105 AZ Amsterdam, The Netherlands.
Vink
Monique
M
Haasnoot
P C Joost
PC
Das
Atze T
AT
Berkhout
Ben
B
D045744:Cell Line, Tumor; D004318:Doxycycline / Q000494:pharmacology; D015693:Gene Products, nef / Q000378:metabolism; D015754:Genes, nef; D005822:Genetic Vectors; D015658:HIV Infections / Q000517:prevention & control*; D015497:HIV-1 / Q000235:genetics* / Q000502:physiology; D006801:Humans; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics* / Q000378:metabolism; D013601:T-Lymphocytes; D014162:Transfection; D014779:Virus Replication; D054311:nef Gene Products, Human Immunodeficiency Virus
D015693:Gene Products, nef; D034741:RNA, Small Interfering; D054311:nef Gene Products, Human Immunodeficiency Virus; D004318:Doxycycline