RNAi as Antiviral Therapy: The HIV-1 Case - RNA Interference from Biology to Therapeutics - page 229

CD34 + hematopoietic progenitor cells. The transplant consisted, for safety
reasons, of a mixture of genetically modified and untreated cells. No infusion-
related toxicities were reported. Persistent gene marking and sustained shRNA and
ribozyme expression were documented in blood cells for up to 24 months [ 96 ] .
Future optimization of the transplant procedure, in particular the preferential infu-
sion of transduced cells, should provide the setting for delivery of therapeutic lev-
els of HIV-resistant cells. Combined with the power of antiviral RNAi approaches,
this strategy remains a promising candidate for development of a durable anti-
HIV-1 gene therapy, especially for a minority patient group that exhausted all
treatment options due to drug toxicity or viral resistance.
We reviewed the current status of the development of an RNAi-based gene ther-
apy to control HIV-1 infection and AIDS disease progression. The potent and
sequence-specific inhibition observed for such RNAi action forms the cornerstone
for such a therapy. The superior transduction of hematopoietic stem cells with len-
tiviral vectors provides the means to deliver the transgene. The availability of sev-
eral lentiviral production facilities is another promising development in the field.
We are currently developing a candidate clinical vector that yielded very potent
antiviral effects in prolonged in vitro cell cultures. It is currently being evaluated for
safety in a humanized mouse model, and we expect to initiate a clinical trial within
the next 3 years.
Acknowledgments RNAi research in the Berkhout lab is sponsored by ZonMw (Translational
gene therapy program) and the Dutch AIDS Fund (grant number 2006006). We also thank the
Belgian Federal Government for financial support through the Inter-University Attraction Pole
grant no. P6/41.
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