Framework programme:

6

Call:

4

Project number:

LSHP-CT-2007-037616

EC contribution:

€ 1,100,000

Duration:

24 Months

Type:

STREP

Starting date:

February 2007

Keywords: HIV-1, LTNP, Genetics, post-genomic, SNP, NK, gamma-delta, T cell, cohort, database

Summary:

A minority (<5%) of hiv-1 infected individuals maintains exceptionally prolonged survival in the absence of clinical symptoms and without antiretroviral therapy; these individuals have been defined here as long term non-progressors (ltnp).

Several cohorts of LTNP have been identified in Europe and elsewhere, and national networks have been formed in France and Italy to better study their particular features. GISHEAL is the first collaborative European consortium aimed at investigating the precise nature of the LTNP state, with particular regard to the host genetic background and gene expression profiling, and to the adaptive and innate immunological responses to the infection. After identification of LTNP by all participants, the GISHEAL common database will be prepared representing the merger of two national (French, Italian) databases together with individual data collected from the UK and Uganda. A genome-wide approach based on screening of 500,000 single-nucleotide polymorphisms (SNP) followed by validation steps, will lead to the potential discovery of novel genetic polymorphisms linked to the LTNP condition, in addition to those already described.

Their effect in terms of gene expression will be studied in different populations of peripheral blood leukocytes (CD4, CD8, monocytes, NK and γδ T cells) using a microfluidic card approach based on multi-parametric real-time PCR (TaqMan) in selected LTNP and chronic progressors (CP) as controls. The adaptive CD4 and CD8 T lymphocyte immune responses of LTNP to HIV-1 will be studied, in comparison to those of viraemic CP. In parallel, the NK cell and γδ T cell responses of LTNP and CP will be investigated. The functional consequences of the potentially novel genetic correlates of LTNP will be also investigated in these immune cells. A multivariate analysis will allow definition of the best correlates of non-progression.

Background:

Although some LTNP show later evidence of disease evolution (usually, a drop of CD4+ T-cell numbers <500 cells/μl blood) and/or have started an antiretroviral regimen, therefore losing their ltnp status, a substantial fraction of them have remained ltnp, providing unique examples of natural control of hiv-1 infection (in some cases exceeding 20 years of infection!). both the genetic and gene expression profile of the host along with his/her innate and adaptive immune responses likely contribute significantly to the establishment and maintenance of the ltnp condition. a central limitation of studies focusing on ltnp consists of their paucity in individual cohorts. a second limitation is the heterogeneity in the evaluation of inclusion and follow-up criteria as well as technical/technological differences among different investigators and centres.

Aim:

The cohorts participating to GISHEAL have been established in 1994-1996 by including individuals who already fitted the original definition of LTNP. Central aim of this project is the creation of the first database encompassing European and African LTNP Cohorts pooling the information already existing at national (France, Italy) and individual Centres in UK and Uganda. This will be the basis for an unprecedented retrospective analysis of correlates of non-progression in the absence of antiretroviral therapy. Given the existence of biorepositories in most of the participating institutions, it will be possible to analyse hostrelated correlates of non-progression regarding the innate and adaptive immune responses and the host genetic and post-genomic backgrounds.

Expected results:

One of the first results of GISHEAL will be the redefinition of the main immunologic and virological parameters correlated to the LTNP condition by the retrospective analysis of the pooled cohorts of the participating members. In addition, the broad genomic and post-genomic approaches will allow the validation and, hopefully, the discovery of novel genetic and epigenetic determinants of nonprogression in HIV-1 disease, while the analysis of the immune response will provide relevant information on the profiles of classical adaptive cell-mediated and innate NK cell and γδ T cell-mediated immune responses of LTNP.

Potential applications:

Identification of genetic, post-genomic and immunological correlates of the LTNP condition will be of great relevance by providing "golden standards" for assessing ongoing vaccine trials as well as for the rationale planning of novel preventive strategies. In addition, they will serve as potential parameters of immunologic reconstitution in therapeutic trials based on both antiretroviral agents and immune-based therapies.

Coordinator:

1 - Guido Poli, M.D.,
Head AIDS Immunopathogenesis Unit,
San Raffaele Scientific Institute,
Via Olgettina n. 58,
20132 Milano
Italy
Tel: 39-02-2643-4909
Fax: 39-02-2643-4905
E-mail: poli.guido@hsr.it
Website: www.sanraffaele.org/Home/index.html

Partners: