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Abstract: Large-scale genomic studies in cohorts have been made possible for the last few years thanks to the progress of molecular biology and bioinformatics. This systematic approach allows a better understanding of the molecular mechanisms of disease development and as a consequence can contribute to the rational design of new diagnostic and therapeutic tools. We present here the exhaustive genotyping of a candidate gene, tumor necrosis factor receptor 1 (TNFR1), in the genetic of resistance to immunodeficiency virus (GRIV) AIDS cohort. This gene was chosen because it is likely to be involved in the apoptosis pathways of CD4+ and CD8+ T-cells during human immunodeficiency virus 1 (HIV-1) infection. Seven frequent polymorphisms were characterized in 319 HIV-1 seropositive patients from the GRIV cohort with extreme disease progression phenotypes, slow progression or rapid progression, and in 427 healthy controls. The TNFR1 gene locus does not appear to be part of any haploblock and contains only a small haploblock of two successive SNPs. One promoter SNP (TNFR1_17444594, position –581) and one intronic SNP (TNFR1_27223241, position +11511) gave weak positive signals of association (resp. P =0.03 and P =0.04) as well as two haplotypes. To our knowledge, this is the first genetic association study dealing with the TNFR1 gene in AIDS and the putative associations identified will need to be validated through other AIDS cohort analyses or by further biological experimentation. [Copyright &y& Elsevier]

Abstract: Members of the secreted phospholipase A2 (PLA2) protein family can inhibit HIV-1 virus replication in vitro. To evaluate the impact of PLA2 gene polymorphisms on AIDS disease development, we studied 12 family members using SNPlex™ technology that permitted simultaneous typing of 70 tagging Single Nucleotide Polymorphisms (tagSNPs). The study utilized HIV-1 seropositive donors with slow progressor (n =168) or rapid progressor (n =54) status, plus 355 control subjects. All donors were Caucasian (total 577 individuals). Genetic associations yielded mainly 0.01< p <0.05, but lower p-values were obtained for four tagSNPs and seven haplotype alleles. These stronger associations corresponded to both secreted (PLA2G2A, PLA2G2D and PLA2G3) and cytosolic (PLA2G4A and PLA2G6) PLA2 genes, including three (PLA2G2A, PLA2G2D and PLA2G4A) implicated in the pathogenesis of other diseases. Our results suggest that the PLA2 gene family may represent genes of interest for a larger study targeting all the known tagSNPs in the PLA2 genes. The data presented in this study will have to be confirmed in other AIDS cohorts and will also be useful for studies undertaken on the PLA2 gene family in other disease cohorts. [Copyright &y& Elsevier]

Abstract: Interleukin-1β (IL-1β) is a crucial cytokine in inflammation processes and has been implicated in the pathogenesis of several chronic inflammatory diseases. Strategies designed to blocking IL-1β by passive administration of inhibitors (mAbs, IL-1 receptor antagonist) have previously demonstrated efficacy in rheumatoid arthritis (RA). Using molecular modelling, we have defined three murine IL-1β peptide regions characterized by their close proximity to the receptor. Synthetic peptides corresponding to these regions, in cyclic and linear form, were delivered as immunogens in Swiss mice, resulting in significant levels of autoantibodies directed against the native murine IL-1β cytokine as determined by ELISA and by an assay for neutralization of IL-1β biological activity. More importantly, one of the cyclic peptides showed a protective effect against inflammation and articular destruction in DBA/1 mouse collagen-induced arthritis, a model of RA. The high rate of success observed for active immunization against cytokine peptides in vivo suggests that the in silico approach to autoantigen design may be a promising avenue for the development of anti-cytokine immunotherapeutics. [Copyright &y& Elsevier]