Human Genomics of Human Immunodeficiency Virus Type 1 and Hepatitis C Virus Infections

Abstract

Recent advances in genetic knowledge, bioinformatics and technology have transformed host genetic research and allowed comprehensive studies of the human genome. Genome-wide association studies based on genotyping arrays have been considered the approach of choice to search for host factors involved in the pathogenesis of chronic viral infections, and to assess their relative contribution. The first part of the thesis describes GWAS of various phenotypes related to HIV infection. Studies of spontaneous viral control affirmed the key role of the HLA region, in modulating viral load and disease progression. We also redefined the known associations between CCR5Δ32 - a 32 base pair deletion in CCR5 - and viral control (in heterozygous individuals), and with HIV resistance (in homozygous individuals). GWAS of HIV acquisition did not identify new associated variant, implying that common genetic polymorphisms with moderate to high effect size do not appreciably impact HIV susceptibility. An additional GWAS looked at T cell responses to an experimental HIV vaccine, showing that the same HLA alleles are implicated in vaccine induced cellular immunity and in natural immune control. Finally, we used variation in the viral genome as phenotype in multiple parallel GWAS. This method allowed the establishment of the first global map of human-HIV genomic interactions, by identifying the areas of the human genome that put pressure on HIV, and the regions of the virus that serve to escape human control. The second part of the thesis presents GWAS performed in patients treated for chronic HCV infection, and investigating the efficacy and toxicity of peg-interferon alpha and ribavirin treatment. Interferon-lambda 3 (encoded by IL28B) was identified as the key determinant of treatment response and ITPA deficiency was shown to play a major protective role against drug-induced anemia. These discoveries were considered major breakthroughs in virology and hepatology: by highlighting host factors that are responsible for differences in pathogenesis, they facilitated the development of diagnostic and therapeutic strategies. The studies presented here provide a detailed description of how common variation influences control of HIV and HCV infections. Still, most of the inter-individual variability remains to be explained. Sequencing strategies will prove essential to better appreciate the global contribution of the human genome to phenotypic outcomes. The ongoing historical transition into the genomic era brings new hopes that host genetics will contribute to a better understanding of viral infections, to the identification of new targets for drug and vaccine development, and to the creation of predictive tools that will make personalized medicine a reality in infectious diseases.