Rationale: Infection with rhinovirus (RV) triggers exacerbations of asthma and chronic obstructive lung disease. Objectives: We sought to develop a mouse model of RV employing RV1B, a minor group serotype that binds to the low-density lipoprotein receptor. Methods: C57BL/6 mice were inoculated intranasally with RV1B, replication-deficient ultraviolet (UV)-irradiated RV1B, or RV39, a major group virus. Measurements and Main Results: Viral RNA was present in the lungs of RV1B-treated mice, but not in those exposed to UV-irradiated RV1B or RV39. Lung homogenates of RV-treated mice contained infectious RV 4 days after inoculation. RV1B exposure induced neutrophilic and lymphocytic airway inflammation, as well as increased lung expression of KC, macrophage-inflammatory protein-2, and IFN-a and IFNb. RV1B-exposed mice showed airway hyperresponsiveness 1 and 4 days after inoculation. UV-irradiated RV1B induced modest neutrophilic airway inflammation and hyperresponsiveness 1 day after exposure. Both RV1B and UV-irradiated RV1B, but not RV39, increased lung phosphorylation of Akt. Confocal immunofluorescence showed colocalization of RV1B and phospho-Akt in the airway epithelium. Finally, pretreatment with the phosphatidylinositol 3-kinase inhibitor LY294002 attenuated chemokine production and neutrophil infiltration. Conclusions: We conclude that RV1B induces airway inflammation in vivo. Evidence is presented that viral replication occurs in vivo and is required for maximal responses. On the other hand, viral replication was not required for a subset of RV-induced responses, including neutrophilic inflammation, airway hyperresponsiveness, and Akt phosphorylation. Finally, phosphatidylinositol 3-kinase/Akt signaling is required for maximal RV1B-induced airway neutrophilic inflammation, likely via its essential role in virus internalization.Keywords: asthma; chronic obstructive pulmonary disease; Akt; low-density lipoprotein receptor Viral infections trigger nearly 80% of asthma exacerbations, and rhinovirus (RV) accounts for the majority of virus-induced exacerbations (1, 2). RV also accounts for a substantial percentage of chronic obstructive pulmonary disease (COPD) exacerbations (3, 4). Understanding of RV-induced exacerbations is incomplete, in part because of the absence of an animal model. Rhinovirus RNA has been detected by polymerase chain reaction (PCR) analysis in lower airway cells from volunteers experimentally infected with RV16 (5, 6) and RV capsid protein has been found in airway epithelial cells, albeit sporadically (6). However, RV has not been cultured from the lower airways of immunocompetent subjects, and therefore the extent to which RV infects or replicates in the lower airways of humans remains unclear.RV, a member of the Picornaviridae family of viruses, is responsible for the majority of common colds. The virus is composed of an icosahedral protein capsid and a positive, singlestranded RNA genome. More than 100 serotypes of RV have been identified. These are divided into two groups on the basis o...