Thèse de doctorat en Génétique et bioinformatique
Sous la direction de Jean-François Zagury.
Soutenue en 2010
à Paris, CNAM .
Pas de résumé disponible.
Genome-wide analyses of the griv chort composed of patients with extreme profile of progression to aids
Pas de résumé disponible.
After 25 years of intensive research, there is still no definitive cure or vaccine for AIDS and molecular mechanisms of AIDS pathogenesis are still not fully elucidated. Nowadays, genotyping by high-density arrays scanning the whole human genome allows discovery of unsuspected genetic risk factors influencing disease development. We performed such a systematic genetic approach on the HIV-1+ patients from the GRIV cohort in order to reveal new leads to fight HIV-1 infection. A first genome-wide association study was carried out by comparing the long-term non-progressors from the GRIV cohort (HIV-1 seropositive and asymptomatic subjects for more than 8 years with no antiretroviral treatment and a CD4 T-cell count consistently above 500/mm3) with seronegative controls. The major role of HLA region both in long-term non-progression and viral load control was thus confirmed. A second genome-wide association study was undertaken by comparing the rapid progressors from the GRIV cohort (HIV-1 seropositive subjects with two or more CD4 T-cell counts below 300/mm3 less than 3 years after the last seronegative testing) with seronegative controls. We identified six independent associations with rapid progression, involving the PRMT6, SOX5, RXRG and TGFBRAP1 genes, which underlies the central role for controlling viral replication and inflammation. Finally, in order to focus on genetic factors impacting on long-term non-progression without controlling viral load at very low level, we performed a genome-wide association study by comparing the long-term non-progressors who were not ‘elites controllers’ (i. E. With a viral load >100 copies/mL) with seronegative controls. A CXCR6 polymorphism was thus highlighted and replicated in three independent cohorts. This association is the sole genome-wide association result confirmed outside the HLA region in the context of HIV-1 infection. These genome-wide approaches unravelled new genetic factors contributing to AIDS pathogenesis, which confirmed the power of this methodology. There is still a need for innovative and alternative bioinformatics strategies to explore these precious data in order to better understand the disease and develop new diagnostic and therapeutic targets.