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In-Depth Information
Chapter 11
RNAi as Antiviral Therapy: The HIV-1 Case
Ben Berkhout and Julia J. M. Eekels
Abstract
RNA interference (RNAi) is a cellular mechanism that mediates sequence-
specific gene silencing. The RNAi mechanism also has therapeutic potential, and it
can be used as an antiviral approach against infectious human pathogens. An attrac-
tive target for RNAi therapeutics is the RNA genome of the human immunodeficiency
virus type 1 (HIV-1). In fact, the first clinical gene therapy trial with a lentiviral vec-
tor that encodes a single RNAi inhibitor in combination with other antiviral RNA
molecules was initiated in early 2008. In this chapter, we will focus on basic mecha-
nistic principles of an RNAi-based attack on HIV-1, which in some respects forms
a formidable target. Among other items, we will discuss target site selection within
the viral RNA genome, the phenomenon of viral escape, and therapeutic strategies
to prevent such escape. Alternatively, one could target cofactors of the host that are
essential for virus replication yet less important for cell physiology. The most
promising anti-escape strategy is the implementation of a combinatorial RNAi
attack on the virus.
11.1
RNAi: Transformation of the Natural Pathway
into a Therapeutic Mode
The development of RNAi-based therapies against a wide variety of diseases,
including cancer, neurological, autoimmune, and infectious diseases was triggered
by the discovery of the RNAi mechanism and RNAi-mediated gene silencing in
B. Berkhout (
*
) • J. J. M. Eekels
Laboratory of Experimental Virology, Department of Medical Microbiology,
Center for Infection and Immunity Amsterdam, Academic Medical Center,
University of Amsterdam , Amsterdam , The Netherlands
e-mail: b.berkhout@amc.uva.nl
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