Schematic representation of HRV genome and polyprotein organization. Processing pattern of rhinovirus polyprotein. All intermediate and final cleavages are carried out by 3C pro and its precursor, 3CD pro , except for the VP0 peptide cleavage into VP4 and VP1, which is done by an as yet unknown protease. Schematic overview of HRV replication cycle.
The RNA synthesis occurs anchored on vesicle membranes. Until recently, the recognized HRV serotypes were classified according to receptor specificity into three groups: The major group with 90 serotypes, whose receptor is intercellular adhesion molecule-1 ICAM-1 ; the minor group with 10 serotypes, whose receptor is the low-density lipoprotein receptor LDLR ; and HRV that shares properties with human enterovirus 68 and utilizes sialic acid residues on cell proteins as receptor.
The range of HRV serotypes and species by the currently accepted classification system, which is based on sequencing and phylogenetic comparisons rather than on receptor usage or antiviral susceptibility, is expected to expand as more sequence information is obtained from field strains. HRV is stable for days on environmental surfaces and is resistant to ethanol, ether, chloroform, and nonionic detergents, but is sensitive to UV light, pH lower than 5, and to halogens, such as chlorine, bromine, iodine, and phenolic disinfectants.
HRV is the predominant agent of ARI in the world and infections occur in people from all continents, including remotely located population groups, such as Bushmen from the Kalahari Desert, native Alaskans, and isolated Amazon Indian tribes.
Rhinoviruses have been clearly shown as frequent cause of colds in the United States and in Western Europe and are frequently associated with ARI in children throughout the world. Evidence suggests that indoor HRV transmission is favored by high relative humidity and crowding of young children, as occurs in the United States at the beginning of the school term, which may explain the autumn seasonal peak of HRV.
HRV transmission requires close exposure and occurs mainly by hand-to-hand contact, followed by self-inoculation into the eye or nose, but can also happen by airborne spread.
Children play a central role in spreading the virus in the household. HRV replication is restricted to the respiratory epithelium, taking place in scattered ciliated cells of the nose and in nonciliated cells of the nasopharynx, and this tropism seems to be a consequence of receptor availability. These, in association with the stimulation of local parasympathetic nerve endings, result in the development of cold symptoms.
Kinins, prostaglandins, proinflammatory cytokines, and chemokines may contribute to vasodilation, increased vascular permeability, influx of polymorphonuclear leukocytes, exocrine gland secretion, and nerve ending stimulation, resulting in nasal obstruction, rhinorrhea, sneezing, cough, and sore throat. Serotype-specific neutralizing IgM, IgG, and IgA antibodies develop in most infected persons in 7—21 days and persist for years.
Protection from infection is partially attributed to the presence of IgA antibody in nasal secretions, and recovery from illness is more dependent on cell-mediated immunity. HRV-induced colds are clinically indistinguishable from colds of other viral etiologies and the main symptoms are nasal discharge, nasal obstruction, sneezing, sore or scratchy throat, hoarseness, cough, and headache.
Facial and ear pressure may be present, but fever and malaise are uncommon. Infants and toddlers may display only nasal discharge and be otherwise asymptomatic. There is no clear association between distinct clinical outcomes and any particular serotypes or species of HRV. The majority of patients have obstruction and mucosal abnormalities of the sinus cavities, eustachian tubes, and the middle ear, which predispose to secondary bacterial sinusitis and otitis media.
HRV is frequently associated with exacerbations of chronic obstructive pulmonary disease and asthma attacks in children over 2 years of age and in adults. In addition to colds, HRV has been increasingly recognized as a major cause of LRTI in children and immunocom- promised hosts, and has been detected over 3 times more often than HRSV in association with wheezing in the first year of life.
Such models will boost the research on pathogenesis and antiviral therapies. HRV can be detected in respiratory secretions by isolation in cultures of susceptible cell lines. Cell lines of primate origin support HRV propagation, but certain strains of HeLa cells and human embryonic fibroblasts provide higher sensitivity for HRV isolation from clinical specimens.
HRV shedding peaks around 48 h after infection and declines rapidly, but may remain at low levels for up to 3 weeks. Unlike other picornaviruses, HRVs are acid-labile, a property that distinguishes them from enteroviruses. Rapid assays for HRV detection, like immunofluorescence and other antigen detection methods, are not available, because of the large number of serotypes. The homotypic nature of HRV antibodies restricts serology to experimental settings.
Real-time PCR multiplex assays directed to conserved sequences of different viral species and genera, as well as recently developed methods such as MultiCode-PLx and Mass-Tag, can detect several viral pathogens in a single run and are expected to become methods of choice for large-scale sample testing in the near future.
Several trials of antiviral agents for HRV have been conducted, but no specific treatment has been licensed, mainly because of the lack of potency, untoward side effects, and drug delivery problems. Symptomatic treatment can be done with a variety of nonprescription medications. Systemic sympathomimetic decongestants may reduce nasal obstruction, first-generation antihistamines may reduce sneezing and rhinorrhea, and nonsteroidal anti-inflammatory drugs may reduce headache, cough, and systemic symptoms.
It may be possible to reduce the exposure to HRV by hand washing after contact with a cold sufferer or after handling objects that may have been contaminated with respiratory secretions.
Application of the virucidal agents, salicylic acid or pyroglutamic acid, to the hands reduced recovery of rhinovirus from the hand skin of treated persons. However, the cost and the local side effects associated with the difficulty to make the drug available to homes in a timely fashion reduce the utility of this approach.
Adenoviruses are nonenveloped, icosahedral DNA viruses of the genus Mastadenovirus , family Adenoviridae. The adenovirus capsid consists of three morphologically, antigenically, and functionally distinct types of capsomere: hexons, penton bases, and penton fibers that project from the penton bases Figure 6. The hexon and penton bases contain complement fixing, group-specific antigens common to all human adenoviruses, whereas the fibers have primarily neutralizing and hemagglutination-inhibiting, type-specific antigens.
Serum neutralization permits the classification of human adenoviruses in 51 distinct serotypes, distributed in six species, A—F. Adenoviruses are commonly accompanied by small, single-stranded DNA parvoviruses known as adeno-associated viruses, which do not seem to cause any specific disease.
Schematic organization of the adenovirus virion. A naked icosahedral capsid contains a double-stranded DNA genome. The main capsid proteins are the hexon II , penton base III , and the penton fiber IV , which projects from each vertex and binds to cell receptor.
The fiber protein binds to the host cell through the protein Coxsackie B and adenovirus receptor CAR , a protein of the immunoglobulin superfamily that serves as high-affinity receptor for the attachment of adenovirus species A, C, D, E, and F.
Plasma membrane protein CD46 is the ligand for the fiber of adenovirus species B. Virus assembly takes place in the nucleus, and the infectious cycle is completed by the release of up to 1 million virions upon cell lysis Figure 7.
Adenovirus replication cycle. After adsorption, virus is internalized by receptor-mediated endocytosis and directed to the nuclear pore where final disassembly occurs. The viral DNA genome is released into the nucleus and the early set of genes are expressed. Early viral gene products mediate further viral gene expression and DNA replication. Then the late viral genes are expressed, generating structural proteins, and assembly of progeny virions occurs.
New viruses are released by cell lysis. Adenoviruses are stable over a wide pH range 5—9 , resistant to isopropyl alcohol, ether, and chloroform. Respiratory diseases are among the most frequent manifestations of infections by adenoviruses, particularly in children under the age of 5 years.
Respiratory infections by adenoviruses occur worldwide and with no apparent seasonality. Outbreaks can occur, especially in crowding conditions, and are more frequent in late winter, spring, and early summer. In adults, adenoviruses occur sporadically and cause mostly URI. In tropical areas, the incidence of adenovirus infections in military recruits is lower, and different serotypes may be involved. Pharyngoconjunctival fever caused by adenoviruses types 3 and 7 may be epidemic or endemic among children during the summer in temperate climates, and has been associated with inadequate chlorination or filtration of swimming pools.
Ocular transmission has also been associated with physician offices where sterilization or hand washing was inadequate. Asymptomatic adenoviral infections and prolonged carrier state are common. Symptomatic infections may involve all parts of the respiratory tract and generally initiate in the upper respiratory epithelium.
Adenovirus infection results in necrosis of cells of airway epithelia and may cause viremia by systemic virus dissemination in immunocompromised persons. Bronchiolitis, interstitial pneumonitis, and mononuclear cell infiltrates are part of the inflammatory process in the lungs. In addition to lytic infection, adenoviruses may become latent in epithelial and lymphoid cells, which is probably important to maintain the virus in populations.
Protection from adenovirus infection and disease is mainly due to type-specific neutralizing antibody, but reinfections, mostly asymptomatic, may occur. A long-lived T-cell immune response develops in most infected immunocompetent persons and is responsible not only for recovery from infection, but also for tissue pathologic changes.
The incubation period of adenovirus infections averages 10 days and the usual symptoms are those of a febrile cold. In children, the fever may be high and long-lasting. Pharyngitis is common and may be associated with fever, pharyngeal exudate, granular appearance of the mucosa, and anterior cervical adenopathy, similarly to streptococcal pharyngitis.
Permanent lung parenchymal damage may occur, especially when adenoviral infection is concurrent with measles.
Clinical manifestations of epidemic adenoviral infections in military recruits may range from colds to severe pneumonia. Typically, the manifestations are fever, pharyngeal symptoms, cough, chest pain, headache, and malaise. Overwhelming pneumonitis may be part of disseminated adenoviral infections in newborn infants and patients with immunodeficiencies, including AIDS. However, the frequent concomitance of other respiratory pathogens in AIDS patients and the high prevalence of asymptomatic adenovirus infection shed doubt on the causal role of the adenovirus in these patients.
Adenoviruses can be detected in respiratory, ocular, or ear secretions, but clinical correlation is required, because asymptomatic virus shedding is common. Isolation of adenoviruses in cell culture with identification by IF has been in use for decades, but direct detection of viral antigens or viral DNA by PCR in clinical samples is a sensitive and rapid alternative.
Adenoviruses replicate well in continuous cell lines of epithelial origin, such as HEp-2, HeLa, and A, and can be adapted to grow in human embryonic lung fibroblasts. In culture, they cause a characteristic CPE and maintenance of cultures for 2 weeks combined with blind passage may increase adenovirus recovery. Inoculation of cells by centrifugation in the shell vial format followed by immunostaining may shorten the detection time.
However, both conventional and real-time PCR are currently accepted as the most sensitive diagnostic methods. Positive results by PCR should be interpreted with caution, given the propensity of adenoviruses to cause latency. Quantitative real-time PCR can also be used to monitor viral load in transplant recipients or immunosuppressed patients, allowing for appropriate interventions to be initiated, such as immunosuppressive regimen adjustment.
Several serologic tests can detect antibodies to the common hexon antigen. However, their clinical utility is restricted. At present, there is no routine effective antiviral treatment for adenovirus infections. Successful therapy of severe adenoviral infections in immunocompromised patients with IV ribavirin has been reported. Trifluridine and cidofovir have shown antiviral effect and in vitro and can potentially be used for treatment.
A live vaccine consisting of wild-type adenovirus packaged in enterically coated capsules induces immunity by ensuring enteric replication without infection of the respiratory tree.
Proper sterilization, hand washing, and chlorination can prevent adenovirus spread via tonometers, hands, and swimming pools. Following that, novel coronaviruses have been discovered. This agent, closely related to coronavirus E, has subsequently been detected in children and adults worldwide.
A second novel coronavirus, subtype HKU1, was detected in from adults with pneumonia in Hong Kong. On the basis of antigenic and genetic studies, the known HCoVs are distributed in two of the three coronavirus groups so far identified. Coronaviruses are enveloped viruses with distinct virion morphology, displaying widely spaced, long petal-shaped spikes at the surface, that confer to the virus a crownlike appearance, origin of the name corona Figure 8.
The viral envelope contains a long helical nucleocapsid with single-, positive-stranded RNA 27—32 kb in size, the largest known viral-RNA genome. Schematic coronavirus structure. HE hemagglutinin , E small envelope protein , and M membrane glycoprotein. The ORF 1 of the genomic RNA is translated into a polyprotein that is processed to yield the proteins that form the transcriptase—helicase complex. The mRNAs direct translation of the viral structural and nonstructural proteins.
Progeny viruses assemble and bud in vesicles between the endoplasmic reticulum and the Golgi apparatus, later released by exocytosis.
Schematic representation of the life cycle of a coronavirus. Virion binds receptors on the plasma membrane by the S glycoproteins resulting in fusion of viral envelope and plasma or endosomal membrane.
The N protein and newly synthesized genomic RNA form the nucleocapsid. Other structural proteins are inserted in the endoplasmic reticulum ER where they are cotranslationally glycosylated and trimerized.
The nucleocapsids are then enclosed by these proteins in the ER and transported to the Golgi apparatus. These viruses break, or lyse, the cell and spread to other cells to continue the cycle. Like the lytic cycle, in the lysogenic cycle the virus attaches to the host cell and injects its DNA. In humans, viruses can cause many diseases. For example, the flu is caused by the influenza virus.
Typically, viruses cause an immune response in the host, and this kills the virus. However, some viruses are not successfully treated by the immune system, such as human immunodeficiency virus, or HIV. This leads to a more chronic infection that is difficult or impossible to cure; often only the symptoms can be treated. Unlike bacterial infections, antibiotics are ineffective at treating viral infections.
Viral infections are best prevented by vaccines, though antiviral drugs can treat some viral infections. Most antiviral drugs work by interfering with viral replication. Some of these drugs stop DNA synthesis, preventing the virus from replicating.
Although viruses can have devastating health consequences, they also have important technological applications. Viruses are particularly vital to gene therapy. Because some viruses incorporate their DNA into host DNA, they can be genetically modified to carry genes that would benefit the host.
Some viruses can even be engineered to reproduce in cancer cells and trigger the immune system to kill those harmful cells. Although this is still an emerging field of research, it gives viruses the potential to one day do more good than harm.
Antibiotics do not stop viruses. Also called the flu. Human Herpesviruses: Biology, Therapy, and Immunoprophylaxis. Cambridge: Cambridge University Press; Related information. Similar articles in PubMed.
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