Five lung transplant recipients were chronically infected with HRV during periods of time ranging from three to 27 months, thus allowing us to study the intra-host genetic variation during natural chronic infections in immunocompromised hosts. Complete Sanger-based and ultra-deep genome sequencing were performed at different time points and sites during infection. Mutation mapping along the HRV genome pointed out that synonymous changes were roughly spread along the entire ORF, whereas non-synonymous changes clustered mostly in the capsid VP2, VP3, and VP1 genes. These capsid genes are also the most variable during acute infections in immunocompetent hosts [37] , as well as the most diverse among the 99 HRV reference types [13] . The VP2, VP3 and VP1 proteins form the outer shell of the virion and are under immune pressure, which explains their fast evolution. The localization of mutation hot spots in these genes in immunocompromised hosts may appear unexpected. However, although these patients are highly immunosuppressed at the time of transplantation, immunosuppressive therapy is then adapted to prevent graft rejection and to preserve a residual cellular and humoral immunity that may account for this observation. This residual immunity is also necessary for the control and recovery of viral and bacterial infections observed in these patients.