AIM-HIV

Introduction

Worldwide, the majority of new HIV infections are due to unprotected sexual intercourses between men and women. Sexual transmission of HIV can be prevented by proper use of condoms and effective antiretroviral treatment of infected patients. Treatment reduces viral load below the limit of detection, reducing drastically the risk of transmission. However, in many countries across the world, access to prevention and treatment is limited. Besides, in these countries women are particularly vulnerable because of gender inequalities and concomitant sexually transmitted infections. Diminishing HIV transmission among women is a key step towards undermine the epidemic, since it will not be transmitted to their partners and to the new generation of children.

Microbicides, compounds that can be applied inside the vagina (or rectum) to prevent HIV transmission, could be a potentially important preventive tool for these populations. Microbicides can give women the opportunity of protecting themselves against HIV when they have little negotiating power to use a condom. To date, no microbicide has been approved for use but there is an important research effort worldwide to develop these drugs.

AIM-HIV is the acronym of “Anti-Inflammatory Microbicides against HIV”, this project has been funded by the 7th Framework Program (FP7) for Research and Technological Development of the European Community. The AIM-HIV consortium is made up of four partners from France, Italy and Spain, and is coordinated by PepeAlcamí. The project has a duration of 30 months starting from December 2012, a total budget of 2,331,804€ and a European Community grant of 1,827,081€.

The main objective of the AIM-HIV project is the development of a microbicide based on 5-Hydroxytyrosol (5HT). This molecule represents a new class of microbicides displaying both antiviral and anti-inflammatory properties that has shown promising preliminary results against HIV in vitro.

The Consortium

The consortium in charge of the project is composed by the four partners, a SME company with broad experience in the field of Hydroxytyrosol, Seprox BIOTECH, and three European research groups with a profound knowledge on HIV pathogenesis: our group in the Instituto de Salud Carlos III (ISCIII), the Commissariat à l’énergie atomique et aux energies alternatives (CEA, France) and the Università Vita-Salute San Raffaele (USR, Italy).

Seprox BIOTECH is a Spanish SME company, born in December 2008, which has developed a unique production process to produce polyphenols based on chemical and enzymatic methods. Polyphenols are some of the most potent natural known antioxidants. Hydroxytyrosol is a polyphenol previously obtained from the olive, from which the purity levels obtained were substantially below to those obtained by Seprox (> 99,5%). Besides, the company has developed a previous project to demonstrate the capacity of Hydroxytyrosol as a HIV integrase blocking agent and to test it in humanised rabbit vaginas, obtaining very promising results. Seprox also has a solid experience in research and product development in the pharmaceutical industry.

In the AIM-HIV project, Seprox is in charge of providing 5-Hydroxytyrosol (5HT) and studying its stability and chemical properties. These activities are included in the work package 4 (Optimized 5HT formulation). In addition, Seprox participates in the work package 6 (Dissemination and exploitation) and has developed an Exploitation Plan for the future commercialization of the new microbicide.

Commissariat à l’énergie atomique et aux energies alternatives (CEA). The Division of Immuno-Virology (DIV) of CEA is in charge of the AIM-HIV project. DIV has acquired strong expertise and skills (more than 15 years ) in viral pathogenesis, treatment for prevention (microbicides, pre- and post-exposure prophylaxis) and vaccine immunology using non-human primate (NHP) models of human viral infections, and has particularly contributed to the development of NHP model of human HIV infection and AIDS.

In the AIM-HIV project, CEA performs the trials in NHP. These activities are included in the work package 3 (Evaluation of the efficacy and pharmacokinetics of 5HT using NHP models).

Università Vita-Salute San Raffaele (USR). The Medical School of this University is the top-rated medical school in Italy. It is intimately linked to the Ospedale San Raffaele (San Raffaele Hospital, 1300 beds) a top-quality private, non-profit hospital. Regarding research activities, physicians, clinical investigators and basic researchers operate together to translate basic research into medical practice, developing new diagnostic tools or therapies.

In the AIM-HIV project, USR is in charge of the study of the anti-inflammatory properties of 5HT. These activities are included in the work package 2 (Immune function and inflammatory potential of 5HT and other antiretroviral drugs).

Description and Objectives

The main objective of the AIM-HIV project is the development of a microbicide based on 5-Hydroxytyrosol (5HT). This molecule represents a new class of microbicides displaying both antiviral and anti-inflammatory properties that has shown promising preliminary results against HIV in vitro.

The final goal of the project is to provide an effective and low-cost new microbicide in order to reduce HIV infection in countries with high incidence of HIV transmission, with special attention to sub-Saharan Africa.

The project has been divided in six work packages (WP):

WP1: Antiviral activity of 5HT and synergism with other microbicides

WP2: Immune function and inflammatory potential of 5HT and other antiretroviral drugs

WP3: Evaluation of the efficacy and pharmacokinetics of 5HT using non-human primate (NHP) models

WP4: Optimized 5HT formulation

WP5: Project management

WP6: Dissemination and exploitation

Pepe Alcamíleads the WP1 (Antiviral activity of 5HT and synergism with other microbicides). The objectives of this WP are to fully analyse the antiviral activity of 5HT against HIV: against different subtypes and circulating recombinant forms, founder virus and resistant viruses; to study its activity in the appropriate cellular contexts involved in HIV transmission; to check its synergism with other antiretroviral drugs that can be used as microbicides; and to characterize its precise mechanism of action.

Pepe Alcamí also leads the two transversal WP: WP5 (Project management) and WP6 (Dissemination and exploitation).

The objectives of WP5 are to promote an optimal use of the knowledge and expertise of the partners in fulfilling the objectives of the project. For this purpose a Quality Assurance Plan has been established. This Plan revises the coordination mechanisms of the consortium, internal and with the European Commission, the monitoring procedures and corrective measures, conflict resolution and ethic topics.

The WP6 is led by ISCIII and Seprox BIOTECH. The objectives of dissemination activities are to promote the generation of new scientific knowledge, public awareness of AIM-HIV project and cross-fertilization between researchers, industry and patients. For these purposes a Dissemination Plan has been designed, including the development of a public website (aim-hiv.isciii.es). Regarding the exploitation activities, Seprox has developed an Exploitation Plan for the future commercialization of the new microbicide, to face up to the huge social and economic impact of the potential project results, granting the access of target population.

Links

Website of the Project: aim-hiv.isciii.es

Partners:

Commissariat à l’énergie atomique et aux energies alternatives (CEA): www.cea.fr/english-portal

Instituto de Salud Carlos III (ISCIII): www.eng.isciii.es

Seprox BIOTECH: www.seprox.es

Università Vita-Salute San Raffaele (USR): www.unisr.it

 

CHAARM

Introduction

Worldwide, the majority of new HIV infections are due to unprotected sexual intercourses. Therefore, traditional and new prevention measures are essential to halt HIV epidemic. Microbicides are compounds that can be applied directly to the vagina or rectum prior to sexual intercourse in order to prevent the transmission of HIV. These compounds are particularly important for women, giving them the opportunity of protecting themselves against HIV when they have little negotiating power to use a condom with their sexual partners.

The fact that microbicides could have a dramatic impact on HIV transmission is indicated by epidemiological modeling performed by the London School of Hygiene and Tropical Medicine. This modeling has indicated that a microbicide that is 60% effective could avoid up to 2.5 million infections worldwide over three years, even if it is only used by a moderate number of people (for example if 20% of people who are in contact with local services in 73 low income countries used a microbicide 50% of the time that a condom is not used).

To date, no microbicide has been approved for use, but there is a considerable research effort worldwide to develop microbicides.

CHAARM is an acronym for “Combined Highly Active Anti-Retroviral Microbicides”. It is a large scale collaborative project co-funded by the European Union under the 7th Framework Programme (FP7) for Research and Technological Development. The consortium is made up of 32 partners and the coordinator is King’s College London. CHAARM will run for 5 years beginning January 2010 and ending December 2014. The project has a budget of 17 million euros with an EC contribution of 12 million euros.

The final purpose of the CHAARM project is to develop combinations of new and existing microbicides which can be applied topically to reduce transmission of HIV during sexual intercourse.

The Consortium

The consortium is made up of 32 partners from academic institutions, research organizations, small and medium enterprises and larger industries, representing 9 different countries in Europe including Ukraine, as well as South Africa and the U.S.A.:

Coordinator:

  • King’s College London, United Kingdom 

Partners:

  • (2) St George’s, University of London, United Kingdom
  • (3) CEA - Commissariat de l’Energie Atomique, Paris, France
    CEA - Division of Immuno-Virology
    CEA - The Chemistry Laboratory for Life Sciences (LCV)
  • (4) Instituut vor Tropische Geneeskunde, Antwerp, Belgium
  • (5) Universiteit Antwerpen, Belgium
    Laboratory of Medicinal Chemistry, UAMC
  • (6) Queen’s University Belfast, United Kingdom
  • (7) Biozentrum, Universität Basel, Switzerland
  • (8) Universita’Degli Studi Di Siena, Italy
  • (9) Katholieke Universiteit Leuven, Belgium
    Laboratory of Virology and Chemotherapy 
    Laboratory for Pharmacotechnology and Biopharmacy
    Laboratory for Molecular Virology and Gene Therapy
  • (10) University College London, United Kingdom
  • (11) Ospedale San Raffaele, Milano, Italy
  • (12) University of York, United Kingdom
  • (13) University Utrecht, the Netherlands
  • (14) Instituto de Salud Carlos III, Madrid, Spain
  • (15) CIC biomaGUNE - Centro de Investigación Cooperativa en Biomateriales, San Sebastian, Spain
  • (16) Council for Scientific and Industrial Research (CSIR), Brummeria, Pretoria, South Africa
  • (17) Universita’Degli Studi Di Roma La Sapienza, Rome, Italy
  • (18) Spoluka Chemical Company Ltd, Kiev, Ukraine
  • (19) Minerva Consulting and Communication, Brussels, Belgium
  • (20) University of Liverpool's Institute of Infection and Global Health, United Kingdom 
  • (21) Polymun Scientific Immunbiologische Forschung GmbH, Vienna, Austria
  • (22) Gilead Sciences Inc, Foster City, CA, United States
  • (23) Particle Sciences Inc, Bethlehem, United States
  • (24) Université De Genève, Geneva, Switzerland
  • (25) International Partnerships for Microbicides, Silver Spring, United States
  • (26) Karolinska Institutet, Stockholm, Sweden
  • (27) European AIDS Treatment Group, Brussels, Belgium
  • (28) Mintaka Foundation pour la Recherche Medicale – Mintaka Foundation for Medical Research, Plan-Les-Ouates, Switzerland
  • (29) Tibotec-Virco Virology, Mechelen, Belgium
  • (30) Microbiotec Srl, Monteriggioni (SI), Italy
  • (31) Middlesex University, London, United Kingdom
  • (32) Imperial College London, United Kingdom

Description and Objectives

The main objective of CHAARM is to develop combinations of highly active microbicides for vaginal and rectal application. The rationale for investigating combinations is both to increase the barrier to development of resistance and to increase efficacy through additive or synergistic effects.

In addition to investigating novel combinations of established compounds, the development of new molecules is proposed, aimed to maintain the pipeline of promising compounds. In parallel, studies of mucosal biomarkers will be performed to determine parameters associated with health and provide a basis for assessments of changes likely to be associated with mucosal damage.

The scientific and technical component of the project comprises 11 work packages. In addition, the project includes a PhD training programme with workshops and laboratory exchanges (WP12), as well as an active dissemination programme (WP13), and a management work package (WP14).

In the CHAARM project, our group contributes to develop the cellular models of HIV infection and to assess the microbicidal activity. Furthermore, we are involved in modelling and in producing specific viral constructs for the evaluation of microbicides. To this aim we have collaborated with the following groups:

Partner 2: Robin Shattock and Carolina Herrera from St George’s, University of London, to evaluate the synergism of different drug combinations using wild type and resistant HIV-1 clones.

Partner 4: Guido Vanham from Instituut vor Tropische Geneeskunde (Institute of Tropical Medicine) in Antwerp, to assess the activity and resistance profile of new NNRTI compounds.

Partner 8: Maurizio Botta from Universita’Degli Studi Di Siena, to evaluate the antiviral activity of new NNRTI and integrase inhibitors.

Partner 15: Soledad Penadés from CICbiomaGUNE - The Centre of Cooperative Research in Biomaterials / Association- San Sebastian, with whom we have developed new platforms based on gold nanoparticles coupled to mannose structures. We have provided the proof of principle about the potential use of these platforms as microbicides (Martínez-Ávila O, et al. Chembiochem. 2009 Jul 20;10(11):1806-9. and Di Gianvincenzo P, et al. Bioorg Med Chem Lett. 2010 May 1;20(9):2718-21.).

Partner18: Spoluka Chemical Company Ltd, Kiev. In collaboration with this company we have screened more than 850 potential CCR5 inhibitors. These compounds were designed in silico and along the CHAARM project an improvement of biological design has been attained following the results of the biological assays performed in our laboratory. Some compounds display anti-HIV activity in the nanomolar range and low toxicity in vitro.

Links

CHAARM oficial website: http://chaarm.eu/

Partners listed in alphabetical order:

 

 

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