Servizio Comunitario di Informazione in materia di Ricerca e Sviluppo - CORDIS


SHIVA Sintesi della relazione

Project ID: 503162
Finanziato nell'ambito di: FP6-LIFESCIHEALTH
Paese: Italy

Final Report Summary - SHIVA (Selection and development of Microbicides for mucosal use to prevent sexual HIV transmission / acquisition)

The main objective of this five year project was the development, up to clinical phase I, of a specific HIV microbicide for the prevention of sexual transmission / acquisition of HIV infection, based on the interruption of viral replication at the mucosal level.

The project has been very productive and successful in many aspects. It is noteworthy that the rational development of two different classes of powerful back-up Non-nucleoside reverse transcriptase inhibitors (NNRTIs), represented by the leads IM46 and YML 220, have been synthesised by the chemist groups of Idenix and SDU, respectively.

None of the above molecules, however, showed antiretroviral properties superior to those of the lead compound MC 1220. As a matter of fact, MC 1220 turned out to be clearly superior not only to its back-up compounds, but also to the other Non-nucleoside reverse transcriptase inhibitors (NNRTIs) (UC 781 and TMC 120) that are currently being developed as microbicides. In fact, in cell-based assays MC 1220 shows outstanding biological properties in terms of potency and spectrum of antiretroviral activity against most of the HIV-1 clades responsible for AIDS all over the world, as well as for its unique capability of irreversibly knocking out the HIV-1 multiplication. Not to mention the fact that, at least in vitro, the 'memory effect' of MC 1220 (i.e. the capability of knocking out the HIV multiplication even after a pre-treatment limited to a few hours before infection and incubation of the infected culture in continuous absence of the drug) is by far the best among the NNRTIs tested, UC 781 and TMC 120 included.

At least in part, the above properties of MC 1220 have been confirmed in the monkey challenge experiments, which represent an additional outstanding achievement of the project. For the first time, in fact, an animal model (consisting of female monkeys challenged with the chimera virus RT-SHIV) has been defined and validated to test the efficacy, alone or in combination with compounds addressing different targets, of the sole class of microbicides so far proved to be able to irreversibly knock out the HIV-1 multiplication: the NNRTIs.

Unfortunately, the first liposomal formulation of the MC-1220 developed in the SHIVA project, provided a 55 % protection at a concentration of 0.5 %. Surprisingly, when the concentration was increased from 0.5 % to 1.5 % the protection did not increase. This was probably due to a high affinity of the drug for liposomes and its low solubility in the aqueous environments.

This result prevented the SHIVA project to proceed, as originally planned, towards clinical experimentation and led to a re-design of activities in order to identify alternative solubilisers of MC-1220, i.e. cyclodextrins, that would increase the solubility of the drug in aqueous media, possibly without causing irritation if administered in the form of a vaginal gel (or emulsion).

In cell-based experiments it was shown that the anti-HIV-1 potency of MC 1220 dissolved in cyclodextrins increased up to 200-fold when compared to that of MC 1220 dissolved in liposomes. Notwithstanding, the new formulation proposed by our partner was not successful providing only a 55 % protection in monkeys.

The partial protection of monkeys, obviously, prevented the consortium to achieve the last planned objective, that is the clinical phase I trials which should have involved the HIV medical teams (consortium partners) already engaged in the development of clinical trial and treatment networks in Africa.

Informazioni correlate


Paolo LA COLLA, (Full Professor)
Tel.: +39-07067-54147
Fax: 390706754210