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Pathogens are undeniably a critical environmental pressure influencing the evolution of humans and other animals; the resulting genetic changes can significantly affect the outcome of an infection [1]. Fossil and genetic evidence suggests that anatomically modern humans (Homo sapiens) arose in Africa approximately 200,000 years ago, following approximately 6 million years of divergence from the shared great ape ancestors of Homo and chimpanzees (Pan troglodytes) [2]. Unlike chimpanzees, who remained confined to their home continent, approximately 60,000 years ago a single human population migrated out of Africa ultimately colonizing Eurasia, the Americas and Oceania. The long period since human–chimpanzee divergence combined with our subsequent worldwide spread has provided ample opportunity for evolution to differentially adapt the two species to novel environments. Hepatitis C virus (HCV), an enveloped positive-sense RNA virus in the family Flaviviridae (genus Hepacivirus), is a blood-borne pathogen that is seemingly restricted to humans [3]. HCV currently infects an estimated 71 million people worldwide (∼1% of the human population) resulting in 399,000 deaths annually due its efficient ability to establish a chronic – typically life long – infection in the liver that can lead to fatal disease decades after primary infection in the absence of treatment. HCV is highly diverse with at least eight distinct ‘genotypes’, which can be over 30% different genetically from each other [4]. While HCV likely originated in the ‘Old World’ – with genotypes endemic only in sub-Saharan Africa and Asia – a precise origin for the virus has not been identified [5]. Estimated timings for the expansion in HCV genomic diversity suggest an origin between hundreds of thousands to thousands of years ago. Thus, current evidence fails to distinguish between whether HCV has a ‘recent’ beginning in humans reflecting independent origins across Africa and Asia or a single more ancient one, with HCV leaving Africa at the time of human migration. This pattern of high genetic diversity in a single host species could be interpreted as evidence of either long-term coexistence of HCV with humans, and/or relatively efficient spillover into humans from an as yet unknown animal reservoir present in Africa and Asia; both scenarios indicate an intrinsic high level of HCV adaptation to humans. Of note, hepaciviral sequences have been found across a very diverse selection of mammals [6] with the greatest diversity found in bats and rodents, yet the closest relative to HCV is one found in horses and dogs but not primates. To explore the virus’ host tropism, HCV has only been inoculated into species belonging to the Euarchontoglires (rodents, rabbits, colugos, treeshrews and primates), for example: mice and woodchucks, treeshrews, and primates (e.g., apes, Old and New World monkeys) [7–10]. Only chimpanzees and, to a much lesser degree, treeshrews are permissive for HCV infection. Using in vivo and in vitro studies the lack of permissivity and susceptibility in lab mice has been mapped to blocked viral entry and immune evasion [7]. Intriguingly, while permissive for chronic HCV infection, rates of chronicity and associated disease differ in chimpanzees and treeshrews when compared with humans. Most notably, HCV-infected chimpanzees have reduced rates of chronicity [11], disease [8], treatment responses [12] and viral glycoprotein gene mutation rates indicative of enhanced immune pressure [13].

Comparative host genomics: how has human evolution affected our immune defence against hepatitis C virus?