The nematode Caenorhabditis elegans is thoroughly studied as a genetic model in the lab since the seventies, yet until ten years ago, little was known about the natural life of the nematode. It is thought that studying the nematode in a natural context can reveal the function of the many genes (>40%) that do not have a known role yet. Moreover, studying allelic variants of genes in wild isolates can have reveal additional molecular mechanisms. In this thesis, the interaction between C. elegans and its natural pathogen the Orsay virus was studied. Viruses and other pathogens impose a strong evolutionary selection pressure and therefore shape the genome of their hosts. This leads to different viral susceptibilities which were indeed observed for different C. elegans strains. Using transcriptomic and quantitative genetic approaches, natural variation in the Intracellular Pathogen Response (IPR), an antiviral defense mechanism, was uncovered. Natural variation in the IPR activity between males and hermaphrodites may also explain why males can be more resistant to Orsay virus infection. Viral infection also changed the behavior of males as they showed more attraction to uninfected than infected hermaphrodites. Clearly, virus infection can affect C. elegans populations at multiple levels. Together, these new insights into host-virus interactions provide better understanding of the natural life of the nematode C. elegans.