Pr Donatien Mavoungou from CRPH Gabon (Centre de Recherche sur les pathologies Hormonales) created in Libreville in 1993, is member of the world Academy of Biomedical technologies. He is an invited scientist at the research Center of the University Hospital of Montreal (Canada) and has been identified Pioneering Author by Biomed Central on the basis of his recent work on the inhibition of Human immunodeficiency virus type 1 (HIV-1) Glycoprotein mediated Cell-Cell fusion by immunor (IM 28) published this year in Virology Journal, printed in USA.

The envelope glycoproteins of HIV-1 is composed of two subunits : a surface glycoprotein gp120 and a transmembrane glycoprotein gp41, which interact with each other in a non covalent manner. Glycoprotein gp120 is critical in attachment of the host cell CD4 receptor, while gp41 contains the fusion sequence.

HIV and SIV require a co-receptor in addition to CD4 for entry into cells. Primary HIV can use a broad range of co-receptor molecules, including CCR1, CCR2b, CCR3, CCR4 and CXCR4 1,2,3.

However, expression of co-receptor together with CD4 on some cell types did not confer susceptibility to infection. Not all human cell type that express an appropriate co-receptor supported virus replication, indicating the presence of other factors influencing viral tropism.

HIV-1 viral entry is inhibited in the presence of the ligands to these chemokine receptors.

Thus RANTES, MIP-1 and MIP-1, the ligand for CCR5, inhibit macrophage-tropic isolates, while SDF-1 envelope glycoproteins to induce cell fusion is an interesting property since molecules which inhibits the fusion process are possible antivirals and may reveal important functional regions either on the viral glycoprotein or on cellular membranes.

Previous studies indicate that a conserved segment of 25 amino acids with hydrophobic character located at the N-terminus of the gp41 transmembrane subunit of the envelop glycoprotein of HIV-1, gp120/41, is involved in the fusion reaction between the viral envelope and the host cell plasma membrane.

Other pieces of evidence have also implicated this sequence in cytopathic process underlying HIV-1 infection of target cells. Initially exposure of this hydrophobic peptide to the aqueous environment in the vicinity of the target cell depends on gp120/41 function.

Activation of this proteins occurs after its interaction with primary receptor CD4 and requires the presence of Human co-factors. According to this model further interaction of the fusion peptide with the cell membrane would depend mainly on the binding capacity of the peptide to the membrane lipid components.

IM 28 has been recently certified as procedure for interleukin 2 and prostaglandin production to improve immunity in human.

Dexamethasone is a glucorticoid ; we have previously shown that it is a potent inhibitor of HIV-1, HIV-2 and SIV mac251 envelope glycoproteins induce phospholipase A2 (PLA2) activation.

This PLA 2 activation was induced after envelop glycoprotein /CD4 interaction and because of its local membrane-destabilizing effect, may have important implications for preparing the cell membrane for fusion with the viral particle.

Glucocorticoids are supposed to be key mediators of neuroendocrine-immune interactions. They are considered to counteract the damaging effect of an over stimulated immune system by exerting an immunosuppressive actions.

On the basis of these observations, it was proposed that these molecules may interfere with the binding with the putative co-receptor. In the present work we have tested the capacity of IM 28 to modify the fusion induced by retroviral glycoproteins as a model for an appropriate anti HIV therapy.

The authors performed a study to evaluate the capacity of IM 28 to inhibit HIV-1 envelope glycoprotein medicated cell fusion using a specific fusion assay. T-cell line expressing stably HIV-1 envelope glycoprotein s was co-cultured with an equal number of T-cell lines expressing CD4 in absence or presence of IM28.

TF228.1.16 which expressed HIV-1 envelope glycoproteins, fuses with 293/CD4 + a T-cell line expressing CD4, inducing numerous large syncytium in absence of corticoids. A concentration of IM 28 between 15 and 45 micro gramme par millilitre was able to completely inhibit this fusion.

Infection of SupT1 cells with TF228.1.16 showed that syncytia appeared more rapidly than those observed in 293/CD4 + cell line. IM28 inhibit syncytia induced by SupT1 infection. These findings support the importance of Env.

Proteins to mediate cell-cell fusion, at least under some experimental conditions, indicates that IM28 inhibit this process and suggest that phospholipase A2 (PLA2) might be necessary for fusion to occur. These date may be helpful in understanding certain aspects of HIV pathogenesis and transmission and for designing an appropriate anti HIV therapy.

Indeed, these findings suggest that IM 28 exerts an inhibitory action on the proteins mediated cell-cell fusion. They also suggest that IM28 interferes with biochemicals processes to stop the progression of existing syncytia leading to the development of a new class of therapeutic doing inhibition of HIV-1 replication was shown previously by Wainberg and Co workers.

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For further information, contact :

Pr Donatien Mavoungou CRPH Libreville - Gabon E-mail : crph2000@yahoo.fr or pdmavoungou@yahoo.com