The views expressed in this article are those of the authors and do not necessarily reflect the official policy or position of the Ministry of Health of Peru, Department of the Navy, Department of Defense, nor the U.S. Government. NAMRU-6 participation was under protocol NMRCD.2002.0019 approved by the Ministry of Health of Peru and the Naval Medical Research Center Institutional Review Board. Disclosure: None of the authors has a financial or personal conflict of interest related to this study. The corresponding author had full access to all data in the study and final responsibility for the decision to submit this publication.  Rhinovirus Genome Variation during Chronic Upper and Lower Respiratory Tract Infections Routine screening of lung transplant recipients and hospital patients for respiratory virus infections allowed to identify human rhinovirus (HRV) in the upper and lower respiratory tracts, including immunocompromised hosts chronically infected with the same strain over weeks or months. Phylogenetic analysis of 144 HRV-positive samples showed no apparent correlation between a given viral genotype or species and their ability to invade the lower respiratory tract or lead to protracted infection. By contrast, protracted infections were found almost exclusively in immunocompromised patients, thus suggesting that host factors rather than the virus genotype modulate disease outcome, in particular the immune response. Complete genome sequencing of five chronic cases to study rhinovirus genome adaptation showed that the calculated mutation frequency was in the range observed during acute human infections. Analysis of mutation hot spot regions between specimens collected at different times or in different body sites revealed that non-synonymous changes were mostly concentrated in the viral capsid genes VP1, VP2 and VP3, independent of the HRV type. In an immunosuppressed lung transplant recipient infected with the same HRV strain for more than two years, both classical and ultra-deep sequencing of samples collected at different time points in the upper and lower respiratory tracts showed that these virus populations were phylogenetically indistinguishable over the course of infection, except for the last month. Specific signatures were found in the last two lower respiratory tract populations, including changes in the 5′UTR polypyrimidine tract and the VP2 immunogenic site 2. These results highlight for the first time the ability of a given rhinovirus to evolve in the course of a natural infection in immunocompromised patients and complement data obtained from previous experimental inoculation studies in immunocompetent volunteers. Human rhinoviruses (HRV) usually cause self-limited upper respiratory tract (URT) illness. However, they are increasingly reported to be associated with complications, such as asthma [1, 2, 3] , chronic obstructive pulmonary disease (COPD) exacerbations [4] , pneumonia, and bronchiolitis in young children [5] . HRVs have the ability to infect the lower respiratory tract (LRT) [6, 7] and can cause chronic infections in immunocompromised hosts [8, 9] . Unlike enteroviruses, most rhinoviruses replicate optimally at lower airway temperatures, which is thought to explain their URT tropism [10] . Rhinovirus strains infecting the LRT may require specific adaptative genomic changes that have not yet been identified.