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SHIVA
HIV/AIDS
Framework programme: 6
Call: 1
Project number:
LSHP-CT-2004-503162
EC contribution: € 3,800,000
Duration: 48 months
Type: IP
Starting date: 1 March 2004
Graphic element Selection and Development of Microbicides for Mucosal Use to Prevent Sexual HIV Transmission/Acquisition
Keywords: Microbicides; HIV; DABOs; MC 1220; NNRTIs; women; clinical trial

Summary:

The main objective of the SHIVA project is to develop MC 1220 up to clinical phase I. This is a novel non-nucleoside inhibitor of the HIV-1 reverse transcriptase, capable of irreversibly knocking out the HIV replication in vitro. The project integrates all the required skills, from chemistry (University of Southern Demark, Odense; Università La Sapienza, Roma; Idenix, Montpellier), to virology (IRD, Montpellier; University of Cagliari), enzymology (CNRS-AMFB, Marseille), pharmaceutical technology (University of Patras), pharmaco-toxicology (Università di Milano; Idenix, Montpellier); primate models (DPZ, Göttingen; CIRMF, Franceville), and clinical research (Hôpital de la Salpétrière, Paris). During the four years of the project, various basic and applied research topics will be addressed.
• Proving the efficacy of MC 1220 in preventing HIV-1 multiplication (reverse transcription and integration) in dendritic cells, macrophages and lymphocytes, i.e. in the primary targets of the virus following its penetration into genital mucosal surfaces. A key goal will be to prove that MC 1220 is effective against the wide variety of HIV-1 belonging to the different groups and subtypes circulating in developing countries.
• Finding the most proper formulation to deliver and accumulate MC 1220 inside the above target cells in the mucosa.
• Proving the efficacy of MC 1220 in protecting the genital mucosae of rhesus monkeys from challenging with a human/simian immunodeficiency virus chimera.
• Starting phase I tolerability clinical trials in HIV positive and negative women.

Background:

The SHIVA project is part of a novel strategy to fight the transmission of HIV by means of products, known as microbicides. Designed for mucosal use, they would provide a convenient and readily available method of self-protection against HIV. Some members of a new class of non-nucleoside reverse transcriptase inhibitors (NNRTIs), the the Dihydro-alkoxy-benzyl-oxopyrimidines (DABOs), proved to be capable of irreversibly knocking out the HIV-1 replication. This property was found to correlate with their ability to bind tightly to the HIV-1 non-nucleoside binding site (NNBS) of reverse transcriptase (RT). The lead compound of this series of ‘tight binding NNRTIs’ is MC1220.

Aim:

The main objective of this four-year project is the development, up to clinical phase I, of a specific HIV microbicide, MC1220, for the prevention of sexual transmission/acquisition of HIV, based on the interruption of viral multiplication at mucosal level.

Expected results:

The final product of this integrated project will consist of an anti-HIV mucosal microbicide candidate available for phase II clinical trials, and endowed with the following characteristics:

• conceived for mucosal application before sexual intercourse and capable of stopping intra cellular HIV replication occurring within the mucosal target cells;
• well tolerated in toxicology models and in women, phase I/II safety studies;
• capable of being produced at a low cost.

Potential applications:

The physical barrier opposed to HIV transmission by latex condoms provides an effective protection against HIV, as well as against the agents of other sexually transmitted diseases. Following topical application at mucosal level, MC 1220 would provide a convenient and readily available method to widen the range of self-protection against HIV at accessible cost, both in developing and industrial countries. Moreover, unlike latex condoms, it would allow women self-protection independence.

Coordinator:

Paolo La Colla
Dipartimento di Scienze e Tecnologie Biomediche, Università degli Studi di Cagliari
Cittadella Universitaria
SS 554-KM4.5
09042 Monserrato, Cagliari
Italy
Tel: +39 070 675 4147
Fax: +39 070 675 4210
E-mail: placolla@unica.it
Website: http://www.unica.it

Partners:

Principal
Scientific
Participants
Official Address Other Information
2Marino ArticoDipartimento di Studi Farmaceutici,
Università degli Studi di Roma ‘La Sapienza’
P.le Aldo Moro, 5
IT-00185 Rome
Italy
Tel: +39 06 4462731
Fax: +39 06 491491
E-mail: artico@uniroma1.it
Website: http://www.medicina1.uniroma1.it/ Sites/index.php?id_sito=655
3Erik
Pedersen
Department of Chemistry,
University of Southern Denmark
Campuvej 55
DK-Odense M
Denmark
Tel: +45 6550 2555
E-mail: ebp@chem.sdu.dk
Website:
http://www.sdu.dk/Nat/Chem/ research/organic/Indexe.html
4Bruno CanardLaboratoire d’architecture et
fonctions des macromolécules biologiques, ESIL-CNRS-AFMB
Case 925, 163 Avenue de Luminy
FR-13288 Marseille Cedex 09
France
Tel: +33 4 91 82 86 44
Fax: +33 4 91 82 86 46
E-mail: bruno@afmb.cnrs-mrs.fr
5Jean Marc
Allaire, Richard Storer
Laboratoires Idenix SARL
170 rue Léon Blum
FR-34000 Montpellier
France
Tel: +33 4 99 52 22 52
Fax: +33 4 99 52 22 50
E-mail: :allaire.jeanmarc@idenix.com
storer.dick@idenix.com
6Sophia
Antimisiaris
Faculty of Pharmacy, University of Patras
University Campus
EL-26500 Achaia
Greece
Tel: +30 2 610 997725
E-mail: Antimisiaris@upatras.gr
Website:http://www.pharmacy.upatras.gr/erg2e.htm
7Gerhart Hunsmann and Christiane Stahl–HennigDepartment for Virology and Immunology,
Deutsches Primate Zentrum
Kellnerweg 4
DE-37077 Göttingen
Germany
Tel: +49 551 3851 150
Fax: +49 551 3851 184
E-mail: ghunsma@gwdg.de Stahlh@dpz.gwdg.de
Website:http://www.dpz.gwdg.de
8Pierre Roques and Pierre RouquetCIRMF
Franceville
Gabon
Tel: +241 67 70 96
E-mail: roques@cirmf.sci.ga
prouquet@yahoo.fr
9Carlo de Giuli MorghenUniversità di Milano
Dip. di Farmacologia Medica
Via Van Vitelli 32
IT-20129 Milan
Italy
Tel: +39 02 5835 7366
Fax: +39 02 5835 6949
E-mail:carlo.degiulimorghen@unimi.it
Website: http://ricerca.unimi.it/
annrpt/rpt2000/DIP0351.htm
10Eric DelaporteIRD Montpellier
911 Avenue Agropolis
FR-34090 Montpellier
France
Tel: +33 4 67 41 62 97
E-mail: eric.delaporte@mpl.ird.fr
Website:
http://www.ird.fr/sais/cgi/TrSaS?nomPopulation=unites&procedure= POPULATION.AfficherObjets&action=ArPAGE&nomObjet=R036
11Christine KatlamaHôpital de la Pitié Salpétrière
Service de Médecine Infectieuse
47-83 Boulevard de l’Hôpital
FR-75651 Paris Cedex 13
France
Tel: +33 1 42 16 01 30
E-mail:
christine.katlama@psl.ap-hop-paris.fr

 
 
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