RNAi as Antiviral Therapy: The HIV-1 Case - RNA Interference from Biology to Therapeutics - page 220

11.1.1 Towards a Durable Gene Therapy

to Control HIV-1 Infection

Candidates for therapeutic intervention include diseases caused by overexpression
of a specific mRNA. RNAi can also be designed to target the RNA genome of
invading microbes such as HIV-1. HIV-1 is a retrovirus that causes a chronic infec-
tion that ultimately leads to disease progression, AIDS, and death. Disease progres-
sion can be halted effectively in most patients with antiviral drugs, but the virus
readily escapes from a monotherapy. A combinatorial drug approach can avoid the
evolution of drug-resistant HIV-1 variants. Despite this clinical success, some prob-
lems remain with multiple drug regimes, including drug-related toxicity that may
show up during long-term follow-up. The goal of alternative gene therapy approaches
against HIV-1 should, therefore, be to durably protect the cells of the immune sys-
tem of an already infected individual against HIV-1 infection. “Intracellular immu-
nization” of these cells, e.g., by means of RNAi technology, should prevent the
depletion of immune cells like CD4 + T cells, monocytes, macrophages, and den-
dritic cells. Maintenance of the immune function during chronic HIV-1 infection
should prevent opportunistic infections and AIDS disease progression.
HIV-1 causes a persistent infection, and therefore, a continuously active treat-
ment seems required. Repeated delivery of exogenous siRNA as anti-HIV therapy
has been proposed based on experiments in a mouse with a humanized immune
system [ 49 ]. Effective virus inhibition was observed with concomitant prevention
of human CD4 + T cell loss. The systemic delivery of siRNA was recently reported
in a human phase I clinical trial via targeted nanoparticles to patients with solid
cancers [ 50 ]. We, however, seriously doubt whether such an siRNA approach would
be suitable in the setting of an HIV-infected patient, where the prevention of viral
escape requires the continuous presence of an effective dose of multiple siRNAs in
all human cell types that can be infected, which are in fact located in many different
tissues and body compartments.
A more effective gene therapy approach would instead trigger the continuous
expression of anti-HIV molecules after a single transduction of HIV-susceptible
cells with an appropriate delivery vector. We believe that the lentiviral vector sys-
tem, which is based on the HIV-1 genome, is particularly attractive for this anti-HIV
action. The lentiviral vector is made replication-incompetent by removal of essen-
tial and pathogenic genes, which were replaced by novel control and therapeutic
sequences. This vector can efficiently infect most target cell types, and transduction
of dividing and nondividing cell types is possible. A major asset for an anti-HIV
approach is the stable integration of the lentiviral vector in the host cell genome,
thus yielding permanent transduction [ 51, 52 ]. This same property raises obvious
safety concerns that will be discussed later.
Use of the HIV-based lentiviral vector system to target the HIV-1 RNA genome
with RNAi reagents can cause some unwanted side effects [ 53 ] . This includes self-
targeting of the vector RNA by the antiviral shRNAs, thus triggering a severe vector
production problem. One can of course select only those anti-HIV shRNAs for
which the target sequences were deleted from the vector genome [ 54 ] . Also miRNA