The objective of ExCellENT-HIT is the exploitation of the cellular pathways
responsible for the nuclear export of unprocessed HIV-1 transcripts, as a novel
anti-HIV therapeutic strategy. The approach is innovative; the objectives are
very clear and focused and achievable within a two year period.
Combination therapies with drugs targeting viral proteins are the current
standard of care for HIV-1 infections. However, drug resistant strains emerge,
resulting in therapeutic failure. Consequently, new anti-HIV drugs are needed,
which should represent novel chemical entities targeting new steps of the HIV
replication cycle. Viruses need the host cellular metabolism in order to
generate a progeny. By targeting cellular co-factors essential for HIV
replication and whose inhibition is not harming the uninfected cells, drug
resistance is less likely to occur.
Nuclear export of unspliced viral RNAs is an essential step of the HIV life
cycle, regulated by the viral protein Rev.
Compelling experimental evidence recently identified the cellular DEAD-box
RNA helicase DDX3 as an essential cofactor for viral mRNA export. Therefore,
the consortium would seek to inhibit the nuclear export of unspliced viral RNAs
activity by a two hit strategy targeting the cellular enzyme DDX3 and the viral
protein Rev, thereby minimising the appearance of drug resistant HIV mutants.
Basic science, biotechnology and provocative chemistry will integrate with the
ultimate goal of targeting the Rev/DDX3 axis by the identification of molecular
decoys that inhibit DDX3 helicase activity, Rev/DDX3 nuclear export and
protein-protein interaction required for Rev/DDX3 function.
The knowledge and technology generated in this project on therapeutic
targeting of nuclear export, protein-protein interaction and helicase activity is
likely to cumulate in hit discovery and will have a wide applicability in the
The ExCellENT-HIT consortium consists of HIV researchers that employ basic
insight into the molecular virology of HIV and use advanced technologies of
post-genomics, bio-informatics and biotechnology. These partners are experts
in Europe to develop new technologies for accelerating anti-HIV drug
development and novel anti-HIV drugs for the health of all people already
infected with HIV or threatened to be infected in Europe and throughout the
world, including people in developing countries. There is a close interaction
between all involved scientific fields (chemistry, modeling, genomics, virology,
structural biology, molecular biology, biochemistry, cell biology,
biotechnology, pharmacology, toxicology) and the related participating
European research laboratories are integrated within these activities.
The ever-expanding AIDS pandemic warrants development of new antiviral
therapeutic strategies for the control of HIV replication. Since HIV replicates
through an error prone reverse transcription step and because of the high
intrinsic replication rate of the virus drug resistant strains frequently emerge,
resulting in therapeutic failure. Consequently, there is a continuing need for
new anti-HIV drugs to be used in combination with the current drugs, which
ideally should represent novel chemical entities targeting steps of the HIV
replication cycle which are still unexploited.
It has been shown that several cellular proteins are employed as essential cofactors
The ExCellENT-HIT project is sharply focused on one step of the viral life cycle,
namely the nuclear export of viral RNAs. This is a crucial step in HIV-1
replication, since the appropriate expression of viral genes paves the way to
all the following steps like encapsidation, virion assembly and budding. Any
drug targeting this step will act at an earlier level than protease inhibitors,
shutting down viral proliferation at a step where no structural viral proteins
(Gag-Pol, Env) or even full length genomic RNA have yet been produced in the
infected cells. Therefore, the ExCellENT-HIT seeks to inhibit the nuclear export
of unspliced viral RNAs activity by a “two hit strategy” targeting the cellular
RNA helicase DDX3 and the viral protein Rev, thereby minimizing the
appearance of drug resistance HIV mutants. ExCellENT-HIT will focus on the
development of new anti-HIV leads, including the pre-clinical testing.
The research consortium will foster a technological platform of academic and
industrial partners that will provide new targets and new assays and might
result in the development of new drugs.
- Impact on health problems and economic impact - AIDS as a major
Since its discovery in the early 1980s, the spread of the acquired immune
deficiency syndrome (AIDS) has taken pandemic proportions. At present, an
estimated 40 million people are living with HIV/AIDS, and since the beginning
of the epidemic 21.8 million individuals have died from the consequences of
the immune deficiency. As a result, AIDS is one of the ten main causes of death
in the world. The large majority of HIV-infected patients live in developing
countries. There is a staggering prevalence in southern Africa. The impact of
the AIDS epidemic affects socioeconomic development of sub-Saharan Africa.
These countries can hardly afford the currently used combination therapies so
price arrangements with pharmaceutical companies are required.
However, also in Europe, AIDS remains an important health problem with new
infections on the rise in many member states. The availability of potent
combination cocktails and a decrease in the number of AIDS deaths may lead
to neglect and an attitude of false security reflecting conquest of the disease
in theWest. The mistake of neglecting the development of new antibiotics two
decades ago because of a false feeling of invincibility toward bacterial
infections in the West, should not be repeated with AIDS. Because of antiviral
resistance and toxicity problems of this life-long therapy, there is a continuous
need to develop new drugs preferentially targeting new targets. Developing
countries would also be helped by the development of antiviral drugs that are
easy to administer in single dose regimens and cause no side effects. Europe
can play an important role here to defend the rights of developing countries.
- Critical mass and European dimension of ExcellENT-HIT
It should be clear that the project's ambitious goals require IP-type (Innovation
Programme) funding (about .1.2 million over two years) to cover the
expenses of at the 5 different partners with different expertise who will each
enrol between one and three scientists on the project. Moreover, expensive
biotechnology and post-genomics (e.g. Fluorescence Correlation
Spectroscopy, Mass Spectrometry) equipment and reagents, and expensive
pre-clinical testing of lead compounds will have to be covered by IP funding.
By funding AIDS research on drug development, targeting early replication
and integration of HIV in Europe, Europe can re-enter the scientific and
biotechnological stage as an important player in the AIDS-field, which is
related to one of the most important health problems with an enormous socioeconomic
impact, but which is also an important market for biotech and
pharma industry. Here again, Europe should show leadership in addressing
at the same time an important societal health problem, a growing biotech and
pharma market, and the problems associated with AIDS in developing
countries and the availability of affordable drugs. Europe will fail to play this
important role if it does not invest in HIV research.