Human rhinoviruses

Abstract

Human rhinoviruses (HRVs), first discovered in the 1950s, are responsible for more than one-half of cold-like illnesses and cost billions of dollars annually in medical visits and missed days of work. Advances in molecular methods have enhanced our understanding of the genomic structure of HRV and have led to the characterization of three genetically distinct HRV groups, designated groups A, B, and C, within the genus Enterovirus and the family Picornaviridae. HRVs are traditionally associated with upper respiratory tract infection, otitis media, and sinusitis. In recent years, the increasing implementation of PCR assays for respiratory virus detection in clinical laboratories has facilitated the recognition of HRV as a lower respiratory tract pathogen, particularly in patients with asthma, infants, elderly patients, and immunocompromised hosts. Cultured isolates of HRV remain important for studies of viral characteristics and disease pathogenesis. Indeed, whether the clinical manifestations of HRV are related directly to viral pathogenicity or secondary to the host immune response is the subject of ongoing research. There are currently no approved antiviral therapies for HRVs, and treatment remains primarily supportive. This review provides a comprehensive, up-to-date assessment of the basic virology, pathogenesis, clinical epidemiology, and laboratory features of and treatment and prevention strategies for HRVs.

Fig 1

HRV genomic structure. HRV is a 7.2-kb single-stranded, positive-sense RNA virus with a single open reading frame joined to a 5′ untranslated region and a short viral priming protein (VPg). The P1 protein is processed to form the HRV capsid, and P2 and P3 are processed to produce VPg, protease, and RNA-dependent RNA polymerase (RDRP) (6). IRES, internal ribosomal entry subunit.

Fig 2

Viral replication in airway epithelial cells. Depending on the receptor type, virus uptake occurs via clathrin-dependent or -independent endocytosis or via macropinocytosis. A drop in the pH leads to viral uncoating. Negative-strand (parental) RNA is replicated as well as translated into structural (capsid) and nonstructural proteins. The virion is then assembled and packaged prior to cellular export via cell lysis (6, 7). LDLR, low-density-lipoprotein receptor; ICAM-1, intercellular adhesion molecule 1.

Fig 3

Signal transduction pathways and activation of the innate immune response. In the endosome, viral dsRNA and ssRNA are recognized by TLR3 and TLR7/8, respectively. An interaction with TLR3 triggers the upregulation of the pattern recognition receptors (retinoic acid-inducible gene 1 [RIG-1] and melanoma differentiation-associated protein 5 [MDA-5]) (RNA helicases) in the intracellular compartment. RIG-1 and MDA-5 also recognize newly synthesized viral dsRNA and ssRNA in the cytoplasm. RIG-1 and MDA-5 stimulate HRV-induced IFN gene expression as well as the increased production of T cell and neutrophil cytokines, including regulated, normal T cell expressed, and secreted (RANTES); IFN-γ-induced protein 10 (IP-10); IL-8; and epithelial cell-derived neutrophil-activating peptide 78 (ENA78). An interaction with TLR7/8 triggers IFN-β and IFN-γ production and activates the NF-κβ pathway. HRV also interacts with TLR2 on the cell surface to initiate a proinflammatory cytokine response via a MyD88-dependent pathway (38, 39). LDLR, low-density-lipoprotein receptor; ICAM-1, intercellular adhesion molecule 1; TIRAP, Toll–interleukin-1 receptor (TIR) domain containing adaptor protein; PMNs, polymorphonuclear leukocytes.

Fig 4

Mechanisms by which HRV increases susceptibility to bacterial infection. (1) HRVs disrupt epithelial cell barrier function by the dissociation of zona occludens 1 (ZO-1) from the tight junction complex via the increased generation of reactive oxygen species (ROS), thereby facilitating the transmigration of bacteria (28). (2) HRVs promote Staphylococcus aureus internalization into non-fully permissive cultured pneumocytes via the increased release of IL-6 and IL-8 and expression of intercellular adhesion molecule 1 (ICAM-1) on neighboring uninfected cells (175). (3) HRVs stimulate Streptococcus pneumoniae adhesion to human tracheal epithelial cells by inducing the surface expression of platelet-activating factor receptor (PAFR) via NF-κβ expression (173) and to nasal epithelial cells via increased gene and protein expression levels of fibronectin, PAFR, and carcinoembryonic antigen-related cell adhesion molecule (174). (4) Compared to non-HRV-activated macrophages, HRV-activated macrophages demonstrate reduced levels of secretion of TNF-α and IL-8 when exposed to bacterial Toll-like receptors (TLRs) (lipopolysaccharide and lipoteichoic acid) (176). SP-1, promoter-specific transcription factor 1.

Fig 5

Phylogenetic tree. Shown are circle phylogram relationships for known genotypes of HRV-A, HRV-B, and HRV-C. The tree was calculated with neighbor-joining methods from aligned, full-genome RNA sequences and rooted with data for human enterovirus species A, B, and C. The outer ring (“1” or “2”) indicates anticapsid drug group types, if known. The inner ring shows members of the major (“M”) (ICAM-1) and minor (“m”) (LDLR) receptor groups. The HRV-C receptor is unknown. Since few HRV-C strains are fully sequenced, the determination of relationships among these genotypes relies on partial VP1 RNA data (bottom left). Bootstrap values (percentages of 2,000 replicates) are indicated at key nodes. (Reprinted from reference with permission of Wolters Kluwer Health/Lippincott Williams & Wilkins.)