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
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
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
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.
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.
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
• well tolerated in toxicology models and in women, phase I/II safety
• capable of being produced at a low cost.
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
Paolo La Colla
Dipartimento di Scienze e Tecnologie Biomediche, Università degli Studi di Cagliari
09042 Monserrato, Cagliari
Tel: +39 070 675 4147
Fax: +39 070 675 4210