PEDIATRICS Vol. 112 No. 2 August 2003, pp. 491-492
siRNA-DIRECTED INHIBITION OF HIV-1 INFECTION
Joseph A Church, MD
Los Angeles, CA
Novina CD, Murray MF, Dykxhoorn DM, et al. Nature Med. 2002;8:681–686
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Purpose of the Study.
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In mammalian cells, DNA is transcribed into RNA. "RNA interference"
is a mechanism of posttranscriptional gene silencing. Short
interfering 21-23-mer double-stranded RNA segments guide messenger
RNA (mRNA) degradation in a sequence-specific fashion. The purpose
of this study was to investigate the feasibility of using siRNA
to suppress the expression of human immunodeficiency virus (HIV)
receptors (CD4), a viral structural protein (Gag) and green
florescent protein substituted for an HIV regulatory protein
(Nef).
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Methods.
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siRNAs specific for CD4, p24 (gag) and green fluorescent protein
mRNAs were prepared. These were transfected in vitro into cell
lines that were permissive for HIV infection. These cell lines
were then infected in vitro and the degree of suppression of
target proteins was measured.
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Results.
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Silencing the expression of CD4 on target cells decreased HIV
entry into target cells. Silencing of Gag polyprotein production
inhibited HIV RNA replication. Silencing of viral regulatory
gene expression (green florescent protein as a substitute for
Nef) reduced viral gene expression in target T-cells.
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Conclusions.
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These results demonstrate that siRNA technology can be used
to suppress multiple steps of the HIV life cycle and have potential
for therapeutic intervention in HIV infection.
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Reviewer’s Comments.
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Advances in molecular biology continue to reveal unique cellular
pathways that may be manipulated for therapeutic intervention.
That RNA interference can occur in human cells has been recognized
for <2 years. Yet, this remarkable technology has already
been harnessed in a model system to demonstrate it’s potential
as a treatment for HIV infection. Highly active retroviral drug
therapy (HAART) has been extraordinarily successful in reducing
HIV-associated morbidity and mortality. However, the rapid emergence
and spread of HIV strains that are resistant to current drugs
strongly support the development of other avenues of intervention.
As with current gene transfer technology, the delivery of therapeutic
nucleic acids into specific target cells will be a great challenge.
PEDIATRICS (ISSN 1098-4275). ©2003 by the American Academy of Pediatrics
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Purpose of the Study.
Methods.
