AIM-HIV PROJECT------------------------Instituto Salud Carlos III
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Main Results

1. Antiviral activity

5HT is active against HIV in vitro in a wide range of situations including systems mimicking the immune synapse (dendritic cell-lymphocytes interaction) which represents the environment where HIV transmission preferentially occurs. We have also studied the two chamber model, a system where we mimic the vaginal (or rectal) barrier in which the virus should move across the epithelial cells to reach its cellular targets. In this system, our results suggest that 5HT is able to inhibit virus mucosal transmission across different types of epithelial cell lines. Finally, we have studied the antiviral activity of the compound in cervical tissue explants, and the results show inhibition of HIV-1 infection.

In addition, 5HT is active against resistant viruses (CCR5 antagonist, NRTIs, NNRTIs, integrase inhibitor and PIs resistant HIV), founder viruses and different HIV subtypes.

We have observed a strong synergism of 5HT and Tenofovir (the microbicide used in the CAPRISA assay) on HIV replication in vitro. These results open the possibility of combining microbicides as a strategy to improve current outcomes.

With regard to the mechanism of action of 5HT, our results suggest that its activity is independent of the viral entry. The compound seems to act at different steps of the viral cycle, 5HT is able to diminish the number of HIV-1 integrated copies and to inhibit HIV transcription. 

 

                            Antiviral activity of 5HT in human lymphocytes

 

5HT activity against infections of peripheral blood mononuclear cells with different HIV subtypes (A, C, D, E, F and G).

2. Toxicity

Toxicity is only reached at a concentration 100 fold above the drug concentration achieving 50% of viral inhibition. Thus, it is difficult to reach toxicity when used at effective concentrations, making the use of 5HT safe.

3. Inflammation

It has been previously reported that 5HT reduces the pro- inflammatory cytokine production in lypopolysaccharide-stimulated THP1 cells (Zhang X, et al. Biol Pharm Bull. 2009 Apr;32(4):578-82.). Our results showed anti-inflammatory activity of 5HT in THP-1 cells through the inhibition of TNF-a expression, therefore validating previous observations.

Consortium members have analyzed the potential anti-inflammatory activity of 5HT in whole blood assays (WBA) and isolated human monocytes from peripheral blood of healthy donors. Firstly, 5HT does not induce pro-inflammatory cytokines and chemokines in either treated whole blood or isolated monocytes. Second, there is a significant decrease of the pro-inflammatory chemokine CCL2 in WBA and monocytes activated with lipopolysaccharide in the presence of 5HT.

We have also studied the effects of 5HT in cervical tissue explants, our results suggest that 5HT is devoid of pro-inflammatory activities up to 400 µM.

4. Formulation and stability studies

Formulation in standard gel composition has been performed and 5HT displays an excellent stability under different environment conditions in this matrix. In addition, a formulation of 5HT+Tenofovir has been carried out together with stability studies.

 

 

NEWS 01  

        

Productive HIV-1 infection of human cervical tissue ex vivo is associated with the secretory phase of menstrual cycle. Read more.    

  

NEWS 02

    

10/01/2014. The partners of the project and the Scientific Advisory Board attended the Progress Meeting of the project in Madrid.  

NEWS 03

   

October 7-10, 2013. ISCIII and SEPROX presented an oral communication and a poster in the AIDS Vaccine Conference. Read more.

 

Instituto de Salud Carlos III. 2013. All rights reserved

This project has received funding from the European Union’s Seventh Framework Programme for research, technological development and demonstration under grant agreement no 305938.

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