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European Consortium (“GISHEAL”) discovers new genetic correlates of natural control of HIV infection |
A consortium financed by the 6th Framework Program of the European Commission (“GISHEAL : Genetic and Immunological Studies on HIV+ European and African LTNP” - http://www.gisheal.eu/index.php) reports in the on-line version of the Journal of Infectious Diseases the discovery of novel single nucleotide polymorphisms (SNPs) linked to the spontaneous control of disease progression in HIV-infected individuals (“Long-term Non Progressors, LTNP”). The consortium, led by Guido Poli from the San Raffaele University and Scientific Institute in Milan, Italy, includes some of the most prominent European scientists in the field, including: Ioannis Theodorou, Brigitte Autran and Patrice Debré (University Pierre et Marie Curie, and Groupe Hospitalier Pitié-Salpetriere, Paris); Dominique Costagliola (INSERM 720, Paris.); Frances Gotch (Imperial College, London, UK); Elisa Vicenzi (San Raffaele Scientific Institute in Milan); Agostino Riva (Senior Author of the paper) and Massimo Galli (University of Milan and “L. Sacco” Hospital of Milan), as well as Pontiano Kaleebu from the MRC unit at Entebbe in Uganda, although African LTNP were not considered in the present study.
GISHEAL gathered a cohort of 144 HIV positive LTNP (very rare subjects, comprising only 1-2% of all infected individuals) and performed a “genome-wide association study (GWAS)” comparing their entire genome to that of a control cohort of 605 infected individuals with no specific pattern of disease evolution. The study revealed 47 allelic variants (“SNPs”) that differentiated LTNP from controls, most of which were located in the so-called “Major Histocompatibility Complex (MHC)” locus. This observation confirmed and extended previous studies on similar, although different cohorts of individuals capable of spontaneously controlling HIV replication in the absence of antiretroviral therapy. All the studies including that from the GISHEAL Consortium confirm that the MHC Class I locus is a crucial component of the natural delay of HIV disease progression; this locus is particularly important for the adaptive T lymphocyte response to infections, generating cells with high specific capacity to recognize and kill infected cells (“cytolytic T lymphocytes”). However, the new study also emphasizes the potential importance of the Class III MHC locus, encoding genes participating in the complementary, natural (“innate”) arm of the immune response to infections that seems to be specifically associated to the LTNP condition.
This study will serve as a basis for further functional investigations of the role of candidate genes in determining the LTNP condition and could also provide valuable information for designing innovative preventative approaches, including vaccines, that could have a wide impact on the curtailment of the HIV-1 pandemic. Currently, there is no European, national or international funding supporting the GISHEAL Consortium but the participants are confident that the paper by Guergnon et al. will stimulate the interest of public and private agencies to support the Consortium as well as similar initiatives aimed at understanding the correlates of natural control of HIV disease progression.
Ref: J. Guergnon et al. “Single nucleotide polymorphism-defined Class I and Class III MHC genetic subregions contribute to natural long-term nonprogression in HIV infection”. J. Infect. Dis. 2012 (on line)
(Each centre may adds a specific part highlighting the individual participants and contribution to the study)
http://jid.oxfordjournals.org/content/early/2012/01/06/infdis.jir833.long
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A European-African partnership to unveil the secrets of natural resistance to HIV disease progression. The recurrently failing attempts of obtaining a minimally protective preventative vaccine underscore the importance of understanding the natural correlates of protection from HIV disease progression. To this goal, a new alliance between African and European scientists and physicians has recently been formed to study which genetic and immunologic factors characterise HIV positive “long-term nonprogressors (LTNP)”. LTNP are rare individuals (1-2% of all infected persons) who control their infection well for several years without the need for antiretroviral therapy, whilst maintaining good general health and relatively high numbers (conventionally >500 cells/µl) of CD4+ T lymphocytes that are otherwise lost in most HIV infected individuals not taking anti-HIV drugs. Studies on such LTNP have already contributed significantly to our understanding of the mechanisms of protection from disease progression, including certain host genetic factors, and mutations in the virus that attenuate its virulence. Unfortunately, most of these studies have been limited by the small numbers of LTNP in individual cohorts followed at different Centres. The wish to overcome these limitations, and the desire of achieving common goals rather than individual success, has fuelled GISHEAL (“Genetic and Immunological Studies on HIV+ European and African LTNP”), the first multicentric project financed with a € 1 million grant for two years (2008-2009) by the European Commission. GISHEAL will merge two established national networks for studying LTNP (financed by the Istituto Superiore di Sanità, ISS, Rome, Italy and by the Agence Nationale de Recherches sur le SIDA, ANRS, France) with a cohort of LTNP identified in London, U.K., and, importantly, with a cohort of African LTNP in Entebbe, Uganda. These cohorts were individually formed in the individual Centres and countries between 1994 and 1997; a recent meeting of the participants to GISHEAL projects the figure of about 250 LTNP from whom relevant biological samples, such as cellular DNA, RNA and leukocytes, will be available. A major current effort of GISHEAL is the completion of the first European-African database dedicated to LTNP and to the collection and proper archive and storage of clinical samples for both ongoing and future studies. A thorough genetic and post-genomic profile of LTNP will be a key goal of GISHEAL that will be pursued by exploiting the most advanced techniques for scanning the entire human genome and for quantifying levels of individual gene expression. Immunological studies will cover both traditional (“adaptive”) and less well studied “innate” mechanisms potentially involved in the protection of LTNP from HIV disease progression. The common goal of all the GISHEAL scientists and physicians is to ensure that novel knowledge stemming from this project will not only advance our understanding of the host mechanisms that protect a minority of individuals from disease progression, but will also contribute to the discovery of preventative and therapeutic strategies for curtailing HIV infection in general. |
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