Development of an Effective RNA Interference-Based
Anti-HIV-1 Therapy Using an SV40-Derived Vector
Keywords: Therapeutic Molecular Vaccination, HIV-1, AIDS, SV40-Vector and RNA
Interference
Summary:
The Acquired Immunodeficiency Syndrome (AIDS) caused by infection with
the human immunodeficiency virus type 1 (HIV-1) is a pandemic continuing to
grow at an alarming rate, despite the availability of highly active anti-retroviral
chemotherapy (HAART). The World Health Organisation (WHO) and
European Union (EU) therefore launched a co-ordinated action program to
combat poverty-related communicable diseases, including AIDS.
In this project a novel therapy for the treatment of individuals infected with
HIV-1 is to be developed. This therapy involves the application of RNA
interference (RNAi) to prevent productive infection of new cells with HIV-1 and
therefore eventually cure infection. An SV40-based vector will be used to
transfer the therapeutic anti-HIV-1 sequence to T-cells of HIV-1 infected
individuals in order to result in long-lasting improvements of their condition.
SV40 vectors are intrinsically safe, transfecting both non-dividing and dividing
cells. In order to use this therapy in developing countries it is essential to keep
the costs and complexity low. A producer cell line will therefore be generated
in order to produce viral vector particles at high titres and focus on a singleadministration,
long-lasting therapeutic molecular vaccination.
The safety and efficacy of the developed therapeutic vaccine will be tested in
vitro and subsequently in vivo using mouse and simian challenge models.
Background:
HAART can be effective; however, resistant viral strains do emerge. Eventually,
these resistant variants can cause AIDS in treatment-resistant patients. A novel
therapy that involves the application of RNA interference (RNAi) to prevent
productive infection of new cells with HIV-1 and thus eventually cure infection
is the aim of this project. So far, RNAi-based inhibition of HIV-1 replication has
been accomplished through the introduction of virus-specific, synthetic short
double-stranded RNAs. These are short interfering RNAs or DNA constructs
encoding short hairpin RNAs. However, their use as therapeutic antiviral
against HIV-1 is limited because of the rapid emergence of virus escape
variants.
In order to solve this durability problem, DNA constructs encoding virusspecific
long hairpin RNAs (lhRNAs) were developed. It was demonstrated
recently that expression of such lhRNAs in target cells provides durable,
sequence-specific and broad-spectrum inhibition of HIV-1 replication.
Aim:
To develop a novel therapy for the treatment of individuals infected with HIV-
1. This therapy involves the application of RNA interference (RNAi) to prevent
productive infection of new cells with HIV-1 and so eventually cure infection.
An SV40-based vector will be used, and the costs and complexity will be kept
low. Therefore a producer cell line will be generated, to produce viral vector
particles at high titres and focus on a single-administration, long-lasting
therapeutic molecular vaccination.
Expected results:
- Proof of safety and efficacy of the developed therapeutic vaccine tested
in vitro and subsequently in vivo using mouse and simian
immunodeficiency virus (SIV)/Cynomolgus macaque models.
- A producer cell line to produce viral vector particles at high titres
Potential applications:
Therapeutic anti-HIV-1 Vaccine.
Partners:
| Nº |
Principal
Scientific
Participants |
Official Address |
Other Information |
| 2 | Dr Ben Berkhout |
AMC,
Meibergdreef 9,
PO box 22660
1100 DD Amsterdam,
The Netherlands
| Tel. +31 20 566 7400
E-mail: e.h.albers@amc.uva.nl
Website: www.amc.nl
|
| 3 | Puri Fortes |
FIMA Avda. Pio XII 55
31008 Pamplona,
Spain
| Tel.+34 948 194700
E-mail: pfortes@unav.es
Website: www.cima.es |
| 4 | Neil Almond |
NIBSC Blanche Lane, South Mimms
EN6 3QG,
Potters Bar,
Great Britain
| Tel. +44 1707 641220
Email: nalmond@nibsc.ac.uk
Website: www.nibsc.ac.uk |
