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HIDDEN HIV CHALLENGE
HIV/AIDS
Framework programme: 6
Call: 2
Project number:
LSHP-CT-2004-012182
EC contribution: € 657,998
Duration: 36 months
Type: STREP
Starting date: 1 January 2005
Graphic element Challenging the Hidden HIV: Understanding the Block on Transcriptional Reactivation to Eradicate Infection
Keywords: AIDS; latency; integration; reactivation; viral factors; cellular factors; chromatin; siRNA

Summary:

Highly active antiretroviral therapy (HAART) has profoundly decreased morbidity and mortality in human immunodeficiency virus type 1 (HIV-1)-infected individuals. Nonetheless, HIV-1 has not been eradicated by HAART. Factors affecting HIV-1 latency present formidable obstacles for therapeutic intervention and the need for novel therapeutic strategies specifically targeting HIV-1 latency has become evident. However, therapeutic targeting of HIV-1 latency requires an understanding of the basic mechanisms regulating viral quiescence and activation. Exploring the scientific possibilities of new therapies targeting HIV-1 latency may hold new promise of eventual HIV-1 eradication.

Background:

HIV-1 infection is a dynamic process involving a continuous round of infection, replication and cell death. Continuous viral replication causes the loss of CD4+ T cells and therefore determines the rate of progression to immunodeficiency in infected individuals. The use of highly active anti-retroviral therapy (HAART) has recently raised the possibility of a cure for HIV-infected individuals. Despite this success, there have been reports of viral rebound after interruption of HAART in infected individuals in whom HIV plasma viremia was undetectable. The persistence of latently infected, resting CD4+ T cells, containing an integrated DNA provirus that is neither visible to the immune system nor accessible to current anti-HIV therapies, seriously challenges the hope of complete viral eradication. This latent reservoir of HIV, in the pool of resting CD4+ T cells, is established rapidly in primary HIV infection and can persist for an extended period of time. Assuming that this reservoir is only 105 cells per individual, it will take 10 to 60 years of HAART treatment (depending on the study) to totally eradicate the virus. Several combinations of activating stimuli induce HIV expression from this pool of latently infected cells. Viewed in this context, it is critical to define the molecular mechanisms involved in the establishment of latency and the reactivation of the viral expression. Recent studies have clearly shown that chromatin is an integral component of HIV replication. First, the heterogeneous structure of cellular chromatin controls viral expression by directly regulating (i) integration site selection, and (ii) transcriptional reactivation. Moreover, interaction between HIV-1 infection and the RNAi/miRNA pathway could result in the establishment and maintenance of HIV-1 latency. These aspects are being investigated within this project.

Aim:

The proposal aims at identifying the key cellular and viral factors that control HIV latency and at exploiting these findings to design specific, small interfering RNAs as a novel therapeutic tool to eradicate HIV-1 infection. Cellular factors that affect HIV-1 latency could be proteins controlling chromatin silencing and transcriptional reactivation through interaction with viral proteins, as well as small interfering RNAs produced naturally in the infected cells that control silencing. Furthermore, we intend to explore the possibility that HIV-1 itself could modulate the cellular siRNA machinery to control its own expression.

Expected results:

In order to approach these topics, a wide array of techniques will be implemented. A proteomic approach will be used to identify cellular factors involved in the control of viral latency and reactivation. The recruitment of these factors to the integrated viral promoter will be monitored by chromatin immunoprecipitation and by highly innovative fluorescent optical tools. Finally, the information gained from these basic studies will be exploited to design specific siRNA targeted to viral latency. Novel ways to deliver and express such siRNAs singularly, and in combination, will be implemented in order to establish a proof of principle of the feasibility of the approach.

Potential applications:

Novel therapeutic strategies specifically targeting HIV-1 latency.

Coordinator:

Monsef Benkirane
Institut de Genetique Humaine, CNRS UPR1142
141 rue de la Cardonille
34396 Montpellier Cedex 5
France
Tel: +33 4 99 61 99 88
Fax: +33 4 99 61 99 92
E-mail: bmonsef@igh.cnrs.fr
Website: http://www.igh.cnrs.fr

Partners:

Principal
Scientific
Participants
Official Address Other Information
2Alessandro MarcelloInternational Centre for Genetic Engineering and Biotechnology (ICGEB)
Padriciano, 99
IT-34012 Trieste
Italy
Tel: +39 040 3757325
Fax: +39 040 226555
E-mail: marcello@icgeb.org
Website: http://www.icgeb.org
3Annick Harel-BellanLaboratoire ‘Oncogenese, Differenciation et Transduction du Signal’
CNRS UPR 9079
Institut Andre Lwoff,
Batiment B, 1er Etage
7 rue Guy Moquet
FR-94800 Villejuif
France
Tel: +33 1 49 58 33 85
Fax: +33 1 49 58 33 07
E-mail: ahbellan@vjf.cnrs.fr
Website: http://www.vjf.cnrs.fr/ial/
4Ben BerkhoutDepartment of Human Retrovirology
Academic Medical Centre,
University of Amsterdam
Meibergdreef 15
NL-1105 AZ Amsterdam
The Netherlands
Tel: +31 20 566 4822
Fax: +31 20 691 6531
E-mail: b.berkhout@amc.uva.nl
Website:
http://www.berkhoutlab.com
5Jørgen KjemsDepartment of Molecular Biology
University of Aarhus
C.F. Møllers Alle
Bldg. 130, Room 404
DK-8000 Aarhus C
Denmark
Tel: +45 8942 2686
Fax: +45 8619 6500
E-mail: kjems@biobase.dk
Website:
http://www.mbio.au.dk/~jk/
6Stephane EmilianiInstitut Cochin
INSERM U567 CNRS UMR 8104
Département des maladies infectieuses
équipe R. Benarous
Bat. Gustave Roussy 6ème étage
27, rue du fbg. Saint Jacques
FR-75014 Paris
France
Tel: +33 1 40 51 65 76
Fax: +33 1 40 51 65 70
E-mail: emiliani@cochin.inserm.fr
Website:
http://www.cochin.inserm.fr

 
 
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