In West Africa, the Acquired Immunodeficiency Syndrome (AIDS) is caused by both types of Human Immunodeficiency Virus HIV-1 and HIV-2 and the majority of people infected with HIV-2 remain healthy for over 15 years. The major goal of this work was to determine and describe genetic variants associated with phenotypic changes at the population level and study their role in pathogenesis and immune response. Studies presented in this thesis were carried out in two well established HIV-2 cohorts in

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... inea Bissau and Gambia. Using recent tools in molecular medicine i.e. sequence-based techniques (SBT) (Chapter 2), we determined and comprehensively described variations at the two most polymorphic regions of the human genome: HLA and KIR gene complexes located on chromosomes 6 and 19, respectively, in these cohorts (Chapters 3 and 6). The data showed high heterogeneity in allele and genotype frequencies between the studied populations. Furthermore, we related the presence of gene variants to HIV-2 antibody status and study their effect on markers of disease progression, notably CD4+ T cell count and viral load (Chapter 4). Here we showed for the first time that HLA-B*1503 associates with poor prognosis after HIV-2 infection and HLA-B*0801 with susceptibility to HIV-2 while the compound genotypes KIR2DL2+HLA-C1 and KIR2DS2+HLA-C1 protect against HIV-2 acquisition in the Manjako ethnic group. None of the HLA class I alleles/haplotypes and KIR gene profiles was found to influence HIV-2 infection in the second cohort, which was of mixed ethnic origin (Chapter 5). In general, we observed that alleles previously shown to be associated with HIV-1 disease in western populations showed no effect in HIV-2 infection. This emphasizes the need to study HLA and HLA/KIR combinations in different populations in order to better inform subsequent vaccine design and evaluation in target populations.