Risk factors Risk factors for development of severe lower<unk>  tract infection with<unk>  vary by population. Population Risk factors for progression to lower<unk>  infection with<unk>  Children *Prematurity *Low birth weight *Male sex *Having older siblings *Maternal smoking during pregnancy *History of atopy (tendency to develop allergic diseases) *No breastfeeding *Household crowding *Congenital heart or lung disease Adults & elderly *Older age (>65 years of age) *Chronic heart or lung (especially COPD) *Functional disability *Residence in a care home Immunocompromised *Lymphopenia *Neutropenia *Graft-versus-host disease *Use of corticosteroids or myeloablative conditioning regimens *Recent hematopoietic stem cell transplant Virology A phylogenetic tree of the pneumovirus & paramyxovirus families Taxonomy<unk>  is a negative-sense, single-stranded RNA virus. The scientific name for this viral species is Human orthopneumovirus. This is synonymous with Human<unk>  (hRSV) and is often shortened to just<unk> . It belongs to the genus Orthopneumovirus, family Pneumoviridae, order Mononegavirales. Its name comes from the fact that F proteins on the surface of the virus cause neighboring cell membranes to merge, creating large multinucleated<unk>  Antigenic subtypes<unk>  is divided into two antigenic subtypes, A and B, based on the reactivity of the F and G surface proteins to monoclonal antibodies. The subtypes tend to circulate simultaneously within local epidemics, although subtype A tends to be more prevalent. Generally,<unk>  subtype A <unk> A) is thought to be more virulent than<unk>  subtype B <unk> B), with higher viral loads and faster transmission time. To date, 16<unk> A and 22<unk> B clades (or strains) have been identified. Among<unk> A, the GA1, GA2, GA5, and GA7 clades predominate; GA7 is found only in the United States. Among<unk> B, the BA clade predominates worldwide. Genome<unk>  structure and genome organization. (a) ~150 nm<unk>  virion particle and (b) single-stranded negative-sense RNA genome consisting of 10 genes (NS1-NS2-N-P-M-SH-G-F-M2-L).<unk>  has a negative-sense, single-stranded RNA genome. The genome is linear and approximately 15,000 nucleotides in length. It is non-segmented which means that, unlike influenza,<unk>  cannot participate in the type of genetic reassortment and antigenic shifts responsible for large pandemics. It has 10 genes encoding for 11 proteins. The gene order is NS1-NS2-N-P-M-SH-G-F-M2-L, with the NS1 and NS2 gene serving as nonstructural promoter genes. Electron micrograph of<unk>  particle, which has variable shapes. Structure & proteins Filamentous<unk>  particles<unk>  is a medium-sized (~150 nm) enveloped virus. While most particles are spherical, filamentous species have also been identified. The genome rests within a helical nucleocapsid and is surrounded by matrix protein and an envelope containing viral glycoproteins. There are 11 proteins, described further in the table below. +RSV proteins and their function and location in the virion Location in the Virion Protein Alternative Name Function Additional Information Lipid envelope (transmembrane surface proteins) G Glycoprotein Viral attachment to ciliated cells of the host airway F and G glycoproteins are the two major surface proteins that control viral attachment and the initial stages of infection. F and G proteins are also the primary targets for neutralizing antibodies during natural infection. F Fusion protein Fusion of viral & host cell membranes; syncytium formation SH Small hydrophobic protein Viroporin; ion channel Participates in cell fusion, but no known neutralizing epitope Inner envelope face M Matrix protein Assembly Ribonucleocapsid N Nuceloprotein RNA-binding Involved in genome transcription, RNA replication, and particle budding P Phosphoprotein Phosphorylation L "Large" protein RNA-dependent RNA polymerase M2-1 - Transcription processivity factor Regulatory M2-2 - Regulation of transcription / RNA replication Nonstructural NS-1 - Involved in evasion of the innate immune system Act by inhibiting apoptosis & inhibiting Type I IFN signaling NS-2 - G protein Surface protein G (glycoprotein) is primarily responsible for viral attachment to host cells. This protein is highly variable between strains. G protein exists in both membrane-bound and secreted forms. The membrane-found form is responsible for attachment by binding to glycosaminoglycans (GAGs), such as heparan sulfate, on the surface of host cells. The secreted form acts as a decoy, interacting with antigen presenting cells to inhibit antibody-mediated neutralization. G protein also contains a CX3C fractalkine-like motif that binds to the CX3C chemokine receptor 1 (CX3CR1) on the surface of ciliated bronchial host cells. This binding may alter cellular chemotaxis and reduce the migration of immune cells into the lungs of infected individuals. G protein also alters host immune response by inhibiting signaling from several toll-like receptors, including TLR4. F protein Surface protein F (fusion protein) is responsible for fusion of viral & host cell membranes, as well as syncytium formation between viral particles. Its sequence is highly conserved between strains. Interestingly, while viral attachment appears to involve both F and G proteins, F fusion occurs independently of G. F protein exists in multiple conformational forms. In the prefusion state (PreF), the protein exists in a trimeric form and contains the major antigenic site Ø. Ø serves as a primary target of neutralizing antibodies in the body. After binding to its target on the host cell surface (its exact ligand remains unclear), PreF undergoes a conformational change during which Ø is lost. This change enables the protein to insert itself into the host cell membrane and leads to fusion of the viral and host cell membranes. A final conformational shift results in a more stable and elongated form of the protein (postfusion, PostF). Opposite of the<unk>  G protein, the<unk>  F protein also binds to and activates toll-like receptor 4 (TLR4), initiating the innate immune response and signal transduction.Schematic image of<unk>  life cycle Replication cycle Following fusion of the viral and host cell membranes, the viral nucleocapsid (containing the viral genome) and the associated viral polymerase are delivered into the host cell cytoplasm. Transcription and translation both occur within the cytoplasm. RNA-dependent RNA polymerase transcribes the genome into 10 segments of messenger RNA (mRNA) which is translated into structural proteins by host cell machinery. During replication of the negative-sense viral genome, RNA-dependent RNA polymerase synthesizes a positive-sense complement called the antigenome. This complementary strand is used as a template to construct genomic negative-sense RNA, which is packaged into nucleocapsids and transported to the plasma membrane for assembly and particle budding.
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